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Ji M, Li L, Yu J, Wu Z, Sheng Y, Wang F. New insights into the function and therapeutic potential of RNA-binding protein TRBP in viral infection, chronic metabolic diseases, brain disorders and cancer. Life Sci 2024; 358:123159. [PMID: 39447729 DOI: 10.1016/j.lfs.2024.123159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP.
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Affiliation(s)
- Minghui Ji
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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2
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Chen X, Du S, Zhang Y, Peng K, Liu L, Wang T, Zhang H, Cai S, Zhu C, Li Y, Tuo W, Wang Y, Wei F, Cai Q. Caspase-mediated AURKA cleavage at Asp 132 is essential for paclitaxel to elicit cell apoptosis. Theranostics 2024; 14:3909-3926. [PMID: 38994036 PMCID: PMC11234276 DOI: 10.7150/thno.97842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 06/14/2024] [Indexed: 07/13/2024] Open
Abstract
Background: Aurora kinase A (AURKA) is a potent oncogene that is often aberrantly expressed during tumorigenesis, and is associated with chemo-resistance in various malignancies. However, the role of AURKA in chemo-resistance remains largely elusive. Methods: The cleavage of AURKA upon viral infection or apoptosis stimuli was assesed by immunoblotting assays in several cancer cells or caspase deficient cell line models. The effect of AURKA cleavage at Asp132 on mitosis was explored by live cell imaging and immunofluorescence staining experiments. The role of Asp132-cleavage of AURKA induced by the chemotherapy drug paclitaxel was investigated using TUNEL, immunohistochemistry assay in mouse tumor xenograft model and patient tissues. Results: The proteolytic cleavage of AURKA at Asp132 commonly occurs in several cancer cell types, regardless of viral infection or apoptosis stimuli. Mechanistically, caspase 3/7/8 cleave AURKA at Asp132, and the Asp132-cleaved forms of AURKA promote cell apoptosis by disrupting centrosome formation and bipolar spindle assembly in metaphase during mitosis. The AURKAD132A mutation blocks the expression of cleaved caspase 3 and EGR1, which leads to reduced therapeutic effects of paclitaxel on colony formation and malignant growth of tumor cells in vitro and in vivo using a murine xenograft model and cancer patients. Conclusions: This study reveals that caspase-mediated AURKAD132 proteolysis is essential for paclitaxel to elicit cell apoptosis and indicates that AURKAD132 is a potential key target for chemotherapy.
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Affiliation(s)
- Xiaoting Chen
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Shujuan Du
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Yulin Zhang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Ke Peng
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Lina Liu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Ting Wang
- Baoji Central Hospital, Baoji, People's Republic of China
- Expert Workstation, Baoji Central Hospital, Baoji, People's Republic of China
| | - Hao Zhang
- Baoji Central Hospital, Baoji, People's Republic of China
| | - Shen Cai
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Caixia Zhu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Youhai Li
- Baoji Central Hospital, Baoji, People's Republic of China
| | - Wen Tuo
- Baoji Central Hospital, Baoji, People's Republic of China
| | - Yuyan Wang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Fang Wei
- ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Qiliang Cai
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganism and Infection, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
- Expert Workstation, Baoji Central Hospital, Baoji, People's Republic of China
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3
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Bibo-Verdugo B, Salvesen G. Evolution of Caspases and the Invention of Pyroptosis. Int J Mol Sci 2024; 25:5270. [PMID: 38791309 PMCID: PMC11121540 DOI: 10.3390/ijms25105270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/08/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
The protein scaffold that includes the caspases is ancient and found in all domains of life. However, the stringent specificity that defines the caspase biologic function is relatively recent and found only in multicellular animals. During the radiation of the Chordata, members of the caspase family adopted roles in immunity, events coinciding with the development of substrates that define the modern innate immune response. This review focuses on the switch from the non-inflammatory cellular demise of apoptosis to the highly inflammatory innate response driven by distinct members of the caspase family, and the interplay between these two regulated cell death pathways.
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Affiliation(s)
- Betsaida Bibo-Verdugo
- Instituto Tecnológico de La Paz, Boulevard Forjadores de Baja California Sur 4720, La Paz 23080, Mexico;
| | - Guy Salvesen
- Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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4
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Liu M, Huang C, Zhou X, Jiang C, Liu S, Gao Y, Kuang L, Lei Z, Jia R, Xu J, Legembre P, Liang X. Membrane-bound CD95 ligand modulates CD19-mediated B cell receptor signaling and EBV activation. J Med Virol 2024; 96:e29440. [PMID: 38299675 DOI: 10.1002/jmv.29440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/02/2024]
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are associated with Epstein-Barr virus (EBV) infection in transplant recipients. Most of lymphoblastoid cell lines (LCLs) derived from EBV-immortalized B cells or PTLDs are sensitive to CD95-mediated apoptosis and cytotoxic T cell (CTL) killing. CD95 ligand (CD95L) exists as a transmembrane ligand (mCD95L) or a soluble form (sCD95L). Using recombinant mCD95L and sCD95L, we observed that sCD95L does not affect LCLs. While high expression of mCD95L in CTLs promotes apoptosis of LCLs, low expression induces clathrin-dependent CD19 internalization, caspase-dependent CD19 cleavage, and proteasomal/lysosomal-dependent CD19 degradation. The CD95L/CD95-mediated CD19 degradation impairs B cell receptor (BCR) signaling and inhibits BCR-mediated EBV activation. Interestingly, although inhibition of the caspase activity restores CD19 expression and CD19-mediated BCR activation, it fails to rescue BCR-mediated EBV lytic gene expression. EBV-specific CTLs engineered to overexpress mCD95L exhibit a stronger killing activity against LCLs. This study highlights that engineering EBV-specific CTLs to express a higher level of mCD95L could represent an attractive therapeutic approach to improve T cell immunotherapy for PTLDs.
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Affiliation(s)
- Mu Liu
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Chenxu Huang
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xingchen Zhou
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Congwei Jiang
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Shuai Liu
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ying Gao
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Linlin Kuang
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zhangmengxue Lei
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ran Jia
- Department of Clinical Laboratory, Children's Hospital of Fudan University, Shanghai, China
| | - Jin Xu
- Department of Clinical Laboratory, Children's Hospital of Fudan University, Shanghai, China
| | - Patrick Legembre
- UMR CNRS 7276, INSERM U1262, University of Limoges, Limoges, France
| | - Xiaozhen Liang
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
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5
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Pellegrini H, Sharpe EH, Liu G, Nishiuchi E, Doerr N, Kipp KR, Chin T, Schimmel MF, Weimbs T. Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction. J Biol Chem 2023; 299:105158. [PMID: 37579949 PMCID: PMC10502374 DOI: 10.1016/j.jbc.2023.105158] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/20/2023] [Accepted: 08/01/2023] [Indexed: 08/16/2023] Open
Abstract
Mutations in the gene encoding polycystin-1 (PC1) are the most common cause of autosomal dominant polycystic kidney disease (ADPKD). Cysts in ADPKD exhibit a Warburg-like metabolism characterized by dysfunctional mitochondria and aerobic glycolysis. PC1 is an integral membrane protein with a large extracellular domain, a short C-terminal cytoplasmic tail and shares structural and functional similarities with G protein-coupled receptors. Its exact function remains unclear. The C-terminal cytoplasmic tail of PC1 undergoes proteolytic cleavage, generating soluble fragments that are overexpressed in ADPKD kidneys. The regulation, localization, and function of these fragments is poorly understood. Here, we show that a ∼30 kDa cleavage fragment (PC1-p30), comprising the entire C-terminal tail, undergoes rapid proteasomal degradation by a mechanism involving the von Hippel-Lindau tumor suppressor protein. PC1-p30 is stabilized by reactive oxygen species, and the subcellular localization is regulated by reactive oxygen species in a dose-dependent manner. We found that a second, ∼15 kDa fragment (PC1-p15), is generated by caspase cleavage at a conserved site (Asp-4195) on the PC1 C-terminal tail. PC1-p15 is not subject to degradation and constitutively localizes to the mitochondrial matrix. Both cleavage fragments induce mitochondrial fragmentation, and PC1-p15 expression causes impaired fatty acid oxidation and increased lactate production, indicative of a Warburg-like phenotype. Endogenous PC1 tail fragments accumulate in renal cyst-lining cells in a mouse model of PKD. Collectively, these results identify novel mechanisms regarding the regulation and function of PC1 and suggest that C-terminal PC1 fragments may be involved in the mitochondrial and metabolic abnormalities observed in ADPKD.
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Affiliation(s)
- Hannah Pellegrini
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Elizabeth H Sharpe
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Guangyi Liu
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA; Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Eiko Nishiuchi
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Nicholas Doerr
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Kevin R Kipp
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Tiffany Chin
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Margaret F Schimmel
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
| | - Thomas Weimbs
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA.
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6
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Reinhardt L, Musacchio F, Bichmann M, Behrendt A, Ercan-Herbst E, Stein J, Becher I, Haberkant P, Mader J, Schöndorf DC, Schmitt M, Korffmann J, Reinhardt P, Pohl C, Savitski M, Klein C, Gasparini L, Fuhrmann M, Ehrnhoefer DE. Dual truncation of tau by caspase-2 accelerates its CHIP-mediated degradation. Neurobiol Dis 2023; 182:106126. [PMID: 37086756 DOI: 10.1016/j.nbd.2023.106126] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/30/2023] [Accepted: 04/12/2023] [Indexed: 04/24/2023] Open
Abstract
Intraneuronal aggregates of the microtubule binding protein Tau are a hallmark of different neurodegenerative diseases including Alzheimer's disease (AD). In these aggregates, Tau is modified by posttranslational modifications such as phosphorylation as well as by proteolytic cleavage. Here we identify a novel Tau cleavage site at aspartate 65 (D65) that is specific for caspase-2. In addition, we show that the previously described cleavage site at D421 is also efficiently processed by caspase-2, and both sites are cleaved in human brain samples. Caspase-2-generated Tau fragments show increased aggregation potential in vitro, but do not accumulate in vivo after AAV-mediated overexpression in mouse hippocampus. Interestingly, we observe that steady-state protein levels of caspase-2 generated Tau fragments are low in our in vivo model despite strong RNA expression, suggesting efficient clearance. Consistent with this hypothesis, we find that caspase-2 cleavage significantly improves the recognition of Tau by the ubiquitin E3 ligase CHIP, leading to increased ubiquitination and faster degradation of Tau fragments. Taken together our data thus suggest that CHIP-induced ubiquitination is of particular importance for the clearance of caspase-2 generated Tau fragments in vitro and in vivo.
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Affiliation(s)
- Lydia Reinhardt
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Fabrizio Musacchio
- Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany
| | - Maria Bichmann
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany
| | - Annika Behrendt
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany
| | - Ebru Ercan-Herbst
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany
| | - Juliane Stein
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Isabelle Becher
- European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany
| | - Per Haberkant
- European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany
| | - Julia Mader
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - David C Schöndorf
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Melanie Schmitt
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Jürgen Korffmann
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Peter Reinhardt
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Christian Pohl
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Mikhail Savitski
- European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany
| | - Corinna Klein
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Laura Gasparini
- AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany
| | - Martin Fuhrmann
- Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany
| | - Dagmar E Ehrnhoefer
- BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany.
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7
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Wang H, Julien O. CaspSites: A Database and Web Application for Experimentally Observed Human Caspase Substrates Using N-Terminomics. J Proteome Res 2023; 22:454-461. [PMID: 36696595 DOI: 10.1021/acs.jproteome.2c00620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
CaspSites is a free-to-use database and web application for experimentally observed human caspase substrates using N-terminomics. It can be accessed and used by all users at the web URL www.caspsites.org. CaspSites stores cleavage site information identified for human caspases 1-9 in lysates and apoptotic cells, collected from their corresponding published studies. The database can be queried, viewed, and exported using the search page of the web application. The main parameters offered are protein substrate, cleavage site (P4-P4') residues, and individual caspase data sets, which can be connected using OR, AND, or NOT logical operators for custom user-built queries. CaspSites will be regularly updated with new experimental findings for understudied caspases, providing researchers insight into the distinctive roles human caspases play in cellular processes by identifying their target proteins in relation to each other.
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Affiliation(s)
- Henry Wang
- Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada
| | - Olivier Julien
- Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada
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8
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Wang JH, Wu C, Lian YN, Liu L, Li XY. Targeting long-term depression of excitatory synaptic transmission for the treatment of neuropathic pain. FEBS J 2022; 289:7334-7342. [PMID: 34528400 DOI: 10.1111/febs.16200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 09/02/2021] [Accepted: 09/14/2021] [Indexed: 01/13/2023]
Abstract
Injury or disease in the somatosensory nervous system may cause broad molecular changes and lead to neuropathic pain. Excitatory synaptic transmission in somatosensory pathways conveys the somatosensory information from the peripheral to the central nervous system. Long-term effects of excitatory synaptic transmission on the pain pathway contribute to neuropathic pain hypersensitivity. Synaptic strength is dynamically regulated and undergoes bidirectional changes, manifested by two primary forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), which are mediated by insertion and endocytosis of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), respectively. Molecular mechanisms of LTP have been extensively studied; on the other hand, the role of AMPAR endocytosis in the pain-related synaptic enhancement is less well known. Recent research in the anterior cingulate cortex reveals that loss of LTD contributes to the maintenance of neuropathic pain, which provides the novel perspective of the mechanism of LTD also being critical for maintaining neuropathic pain. More importantly, exploring the molecular mechanism of LTD may help with the development of novel analgesic strategies to manage neuropathic pain.
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Affiliation(s)
- Jing-Hua Wang
- Department of Neurobiology, School of Medicine, Zhejiang University, Hangzhou, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Wu
- Department of Neurobiology, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan-Na Lian
- Department of Neurobiology, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Liu
- Core Facilities of the School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiang-Yao Li
- Department of Neurobiology, School of Medicine, Zhejiang University, Hangzhou, China.,NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.,Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
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9
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Bibo-Verdugo B, Salvesen GS. Caspase mechanisms in the regulation of inflammation. Mol Aspects Med 2022; 88:101085. [PMID: 35248371 DOI: 10.1016/j.mam.2022.101085] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 02/22/2022] [Accepted: 02/26/2022] [Indexed: 12/31/2022]
Abstract
Regulated cell death is defined as genetically encoded pathways that lead towards the demise of cells. In mammals, cell demise can be either inflammatory or non-inflammatory, depending on whether the mechanism of death results in cell rupture or not. Inflammatory cell death can lead towards acute and chronic disease. Therefore, it becomes important to distinguish the mechanisms that result in these different inflammatory cell death outcomes. Apoptosis is a non-inflammatory form of cell death where cells resist rupture. In contrast, pyroptosis and necroptosis are inflammatory forms of cell death principally because of release of pro-inflammatory mediators from cells undergoing lysis. This review focusses on the mechanisms of these different cell death outcomes with specific emphasis on the caspase family of proteolytic enzymes.
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Affiliation(s)
- Betsaida Bibo-Verdugo
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
| | - Guy S Salvesen
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
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10
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Fretwurst T, Tritschler I, Rothweiler R, Nahles S, Altmann B, Schilling O, Nelson K. Proteomic profiling of human bone from different anatomical sites - A pilot study. Proteomics Clin Appl 2022; 16:e2100049. [PMID: 35462455 DOI: 10.1002/prca.202100049] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 12/30/2022]
Abstract
PURPOSE The study aim is a comparative proteome-based analysis of different autologous bone entities (alveolar bone [AB], iliac cortical [IC] bone, and iliac spongiosa [IS]) used for alveolar onlay grafting. EXPERIMENTAL DESIGN Site-matched bone samples of AB, IC, and IS were harvested during alveolar onlay grafting. Proteins were extracted using a detergent-based (sodium dodecyl sulfate) strategy and trypsinized. Proteome analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). MaxQuant was used for peptide-to-spectrum matching, peak detection, and quantitation. Linear models for microarray analysis (LIMMA) were used to detect differentially abundant peptides and proteins. RESULTS A total of 1730 different proteins were identified across the 15 samples at a false discovery rate of 1%. Partial least-squares discriminant analysis approved segregation of AB, IC, and IS protein profiles. LIMMA statistics highlighted 66 proteins that were more abundant in AB then in IC (vs. 92 proteins were enriched in IC over AB). Gene Ontology enrichment analysis revealed a matrisomal versus an immune-related proteome fingerprint in AB versus IC. CONCLUSION AND CLINICAL RELEVANCE This pilot study demonstrates an ECM protein-related proteome fingerprint in AB and an immune-related proteome fingerprint in IS and IC.
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Affiliation(s)
- Tobias Fretwurst
- Department of Oral- and Craniomaxillofacial Surgery/Translational Implantology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | | | - René Rothweiler
- Department of Oral- and Craniomaxillofacial Surgery/Translational Implantology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Susanne Nahles
- Department of Oral and Maxillofacial Surgery, Berlin Institute of Health, Corporate Member of Freie Universität Berlin, Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Brigitte Altmann
- Department of Prosthetic Dentistry, Center for Dental Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,G.E.R.N Center for Tissue Replacement, Regeneration & Neogenesis, Department of Prosthetic Dentistry, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Oliver Schilling
- Institute of Surgical Pathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Katja Nelson
- Department of Oral- and Craniomaxillofacial Surgery/Translational Implantology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
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11
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Chen J, Wang S, Blokhuis B, Ruijtenbeek R, Garssen J, Redegeld F. Cell Death Triggers Induce MLKL Cleavage in Multiple Myeloma Cells, Which may Promote Cell Death. Front Oncol 2022; 12:907036. [PMID: 35965541 PMCID: PMC9369655 DOI: 10.3389/fonc.2022.907036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/10/2022] [Indexed: 11/24/2022] Open
Abstract
Necroptosis is a type of caspase-independent programmed cell death that has been implicated in cancer development. Activation of the canonical necroptotic pathway is often characterized with successive signaling events as the phosphorylation of mixed lineage kinase domain-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3), followed by MLKL oligomerization and plasma membrane rupture. Here, we demonstrate that omega-3 polyunsaturated fatty acids DHA/EPA and the proteasome inhibitor bortezomib induce necroptosis in human multiple myeloma (MM) cells in a RIPK3 independent manner. In addition, it seemed to be that phosphorylation of MLKL was not essential for necroptosis induction in MM cells. We show that treatment of MM cells with these cytotoxic compounds induced cleavage of MLKL into a 35 kDa protein. Furthermore, proteolytic cleavage of MLKL was triggered by activated caspase-3/8/10, and mutation of Asp140Ala in MLKL blocked this cleavage. The pan-caspase inhibitor ZVAD-FMK efficiently prevented DHA/EPA and bortezomib induced cell death. In addition, nuclear translocation of total MLKL and the C-terminus were detected in treated MM cells. Collectively, this present study suggests that caspase-mediated necroptosis may occur under (patho)physiological conditions, delineating a novel regulatory mechanism of necroptosis in RIPK3-deficient cancer cells.
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Affiliation(s)
- Jing Chen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | | | - Bart Blokhuis
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | | | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Nutricia Research, Utrecht, Netherlands
| | - Frank Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- *Correspondence: Frank Redegeld,
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12
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Bąchor R. Peptidyl-Resin Substrates as a Tool in the Analysis of Caspase Activity. Molecules 2022; 27:molecules27134107. [PMID: 35807352 PMCID: PMC9268085 DOI: 10.3390/molecules27134107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 02/04/2023] Open
Abstract
Caspases, proteolytic enzymes belonging to the group of cysteine proteases, play a crucial role in apoptosis. Understanding their activity and substrate specificity is extremely important. Fluorescence-based approaches, including fluorogenic substrates, are generally used to confirm cleavage preferences. Here we present a new method of substrate specificity and activity analysis based on the application of fix-charge tagged peptides located on the resin. The proteolysis of peptide bond on the resin, occurring even with low efficiency, results in the formation of N-terminal fragments of model peptide containing ionization enhancers in the form of quaternary ammonium groups, allowing for ultrasensitive and reliable analysis by LC-MS/MS. The possibility of application of the proposed solution was tested through the analysis of substrate specificity and activity of caspase 3 or 7. The obtained results confirm the known substrate specificity of executioner caspases. Our solution also allowed us to observe that caspases can hydrolyze peptides shorter than those presented to date in the scientific literature.
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Affiliation(s)
- Remigiusz Bąchor
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wrocław, Poland
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13
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Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer. Sci Rep 2022; 12:4028. [PMID: 35256749 PMCID: PMC8901631 DOI: 10.1038/s41598-022-08051-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/28/2022] [Indexed: 11/08/2022] Open
Abstract
Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates.
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14
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Abou Zeid LY, Shanmugapriya S, Rumney RL, Mosser DD. Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression. Cell Stress Chaperones 2022; 27:11-25. [PMID: 34719748 PMCID: PMC8821752 DOI: 10.1007/s12192-021-01242-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/21/2021] [Accepted: 10/01/2021] [Indexed: 10/19/2022] Open
Abstract
Cells respond to stress through adaptive mechanisms that limit cellular damage and prevent cell death. MicroRNAs act as regulators of stress responses and stress can impact the functioning of miRNA biogenesis pathways. We were interested in the effect that severe proteotoxic stress capable of inducing apoptosis may have on miRNA biogenesis and the impact of the molecular chaperone protein HSP70 under these conditions. We found that the miRNA processing enzymes Drosha and Dicer and their accessory proteins DGCR8 and TRBP2 are cleaved by caspases in apoptotic cells. Overexpression of HSP70 prevented caspase activation and the degradation of these processing proteins. Caspase cleavage of TRBP2 was mapped to amino acid 234 which separates the two dsRNA-binding domains from the C-terminal Dicer interacting domain. Overexpression of TRBP2 was found to increase miRNA maturation, while expression of either of the fragments generated by caspase cleavage impaired maturation. These results indicate that inactivation of miRNA biogenesis is a critical feature of apoptosis and that cleavage of TRBP2, rather than simply a loss of function, serves to create positive acting inhibitors of pre-miRNA maturation.
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Affiliation(s)
- Lina Y Abou Zeid
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
| | | | - Rebecca L Rumney
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
| | - Dick D Mosser
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
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15
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Lee SH, Jung S, Lee YJ, Hyun M, Chung KC. FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity. J Biol Chem 2021; 297:101426. [PMID: 34800438 PMCID: PMC8665361 DOI: 10.1016/j.jbc.2021.101426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 11/05/2021] [Accepted: 11/15/2021] [Indexed: 01/26/2023] Open
Abstract
Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene (Fbxo7) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8-knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.
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Affiliation(s)
- Su Hyoun Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Sungyeon Jung
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Yun Ju Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Minju Hyun
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Kwang Chul Chung
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
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16
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Shrestha S, Clark AC. Evolution of the folding landscape of effector caspases. J Biol Chem 2021; 297:101249. [PMID: 34592312 PMCID: PMC8628267 DOI: 10.1016/j.jbc.2021.101249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/07/2022] Open
Abstract
Caspases are a family of cysteinyl proteases that control programmed cell death and maintain homeostasis in multicellular organisms. The caspase family is an excellent model to study protein evolution because all caspases are produced as zymogens (procaspases [PCPs]) that must be activated to gain full activity; the protein structures are conserved through hundreds of millions of years of evolution; and some allosteric features arose with the early ancestor, whereas others are more recent evolutionary events. The apoptotic caspases evolved from a common ancestor (CA) into two distinct subfamilies: monomers (initiator caspases) or dimers (effector caspases). Differences in activation mechanisms of the two subfamilies, and their oligomeric forms, play a central role in the regulation of apoptosis. Here, we examine changes in the folding landscape by characterizing human effector caspases and their CA. The results show that the effector caspases unfold by a minimum three-state equilibrium model at pH 7.5, where the native dimer is in equilibrium with a partially folded monomeric (PCP-7, CA) or dimeric (PCP-6) intermediate. In comparison, the unfolding pathway of PCP-3 contains both oligomeric forms of the intermediate. Overall, the data show that the folding landscape was first established with the CA and was retained for >650 million years. Partially folded monomeric or dimeric intermediates in the ancestral ensemble provide mechanisms for evolutionary changes that affect stability of extant caspases. The conserved folding landscape allows for the fine-tuning of enzyme stability in a species-dependent manner while retaining the overall caspase–hemoglobinase fold.
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Affiliation(s)
- Suman Shrestha
- Department of Biology, University of Texas at Arlington, Arlington, Texas, USA
| | - A Clay Clark
- Department of Biology, University of Texas at Arlington, Arlington, Texas, USA.
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17
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Caspases Switch off the m 6A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus. mBio 2021; 12:e0170621. [PMID: 34425696 PMCID: PMC8406275 DOI: 10.1128/mbio.01706-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Our study establishes that caspase disarming of the m6A RNA modification machinery fosters EBV replication. IMPORTANCE The discovery of an N6-methyladenosine (m6A) RNA modification pathway has fundamentally altered our understanding of the central dogma of molecular biology. This pathway is controlled by methyltransferases (writers), demethylases (erasers), and specific m6A binding proteins (readers). Emerging studies have linked the m6A RNA modification pathway to the life cycle of various viruses. However, very little is known regarding how this pathway is subverted to benefit viral replication. In this study, we established an unexpected linkage between cellular caspases and the m6A modification pathway, which is critical to drive the reactivation of a common tumor virus, Epstein-Barr virus (EBV).
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18
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Abstract
DEAD (Glu-Asp-Ala-Glu) box RNA helicases have been proven to contribute to antiviral innate immunity. The DDX21 RNA helicase was identified as a nuclear protein involved in rRNA processing and RNA unwinding. DDX21 was also proven to be the scaffold protein in the complex of DDX1-DDX21-DHX36, which senses double-strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleaves DDX21 at D126 and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the interferon beta (IFN-β) signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus.
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19
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Winter N, Novatchkova M, Bachmair A. Cellular Control of Protein Turnover via the Modification of the Amino Terminus. Int J Mol Sci 2021; 22:ijms22073545. [PMID: 33805528 PMCID: PMC8037982 DOI: 10.3390/ijms22073545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
The first amino acid of a protein has an important influence on its metabolic stability. A number of ubiquitin ligases contain binding domains for different amino-terminal residues of their substrates, also known as N-degrons, thereby mediating turnover. This review summarizes, in an exemplary way, both older and more recent findings that unveil how destabilizing amino termini are generated. In most cases, a step of proteolytic cleavage is involved. Among the over 500 proteases encoded in the genome of higher eukaryotes, only a few are known to contribute to the generation of N-degrons. It can, therefore, be expected that many processing paths remain to be discovered.
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Affiliation(s)
- Nikola Winter
- Max Perutz Labs, Department of Biochemistry and Cell Biology, University of Vienna, A-1030 Vienna, Austria;
| | - Maria Novatchkova
- Vienna BioCenter, Research Institute of Molecular Pathology, A-1030 Vienna, Austria;
- Vienna BioCenter, Institute of Molecular Biotechnology, A-1030 Vienna, Austria
| | - Andreas Bachmair
- Max Perutz Labs, Department of Biochemistry and Cell Biology, University of Vienna, A-1030 Vienna, Austria;
- Correspondence:
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20
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Park S, Jeon JH, Park JA, Choi JK, Lee Y. Cleavage of HSP90β induced by histone deacetylase inhibitor and proteasome inhibitor modulates cell growth and apoptosis. Cell Stress Chaperones 2021; 26:129-139. [PMID: 32869129 PMCID: PMC7736425 DOI: 10.1007/s12192-020-01161-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/18/2020] [Accepted: 08/25/2020] [Indexed: 10/23/2022] Open
Abstract
HSP90, one of the molecular chaperones, contributes to protein stability in most living organisms. Previously, we found cleavage of HSP90 by caspase 10 in response to treatment with histone deacetylase inhibitor or proteasome inhibitor in leukemic cell lines. In this study, we investigated this phenomenon in various cell lines and found that HSP90 was cleaved by treatment with SAHA or MG132 in 6 out of 16 solid tumor cell lines. To further investigate the effects of HSP90 cleavage on cells, we introduced mutations to the potential cleavage sites of HSP90β and found that the 294th aspartic acid residue of the protein was mainly cleaved. In the K562 and Mia-PaCa-2 cell lines expressing HSP90β D294A, the cleavage of HSP90 by the treatment with SAHA or MG132 was reduced compared with the K562 and Mia-PaCa-2 cell lines expressing HSP90β WT. Accordingly, cell growth and survival were enhanced by HSP90β D294A expression. Therefore, we suggest that HSP90 cleavage widely occurs in several cell lines, and cleavage of HSP90 may have a potential for one of the mechanisms involved in the anti-tumor effects of known drugs and novel anti-tumor drug candidates.
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Affiliation(s)
- Sangkyu Park
- Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Jae-Hyung Jeon
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Jeong-A Park
- Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Jun-Kyu Choi
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Younghee Lee
- Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, 1 Chungdae-Ro, Seowon-Gu, Cheongju, Chungbuk, 28644, Republic of Korea.
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21
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Wang YJ, Liu MG, Wang JH, Cao W, Wu C, Wang ZY, Liu L, Yang F, Feng ZH, Sun L, Zhang F, Shen Y, Zhou YD, Zhuo M, Luo JH, Xu TL, Li XY. Restoration of Cingulate Long-Term Depression by Enhancing Non-apoptotic Caspase 3 Alleviates Peripheral Pain Hypersensitivity. Cell Rep 2020; 33:108369. [PMID: 33176141 DOI: 10.1016/j.celrep.2020.108369] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 08/09/2020] [Accepted: 10/20/2020] [Indexed: 10/23/2022] Open
Abstract
Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of ∼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.
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Affiliation(s)
- Yong-Jie Wang
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China; Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, and The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Ming-Gang Liu
- Collaborative Innovation Centre for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jing-Hua Wang
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Wei Cao
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Cheng Wu
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Zi-Yue Wang
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Li Liu
- Core Facilities of the School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Fan Yang
- Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China
| | - Zhi-Hui Feng
- Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, and The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Li Sun
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Fuxing Zhang
- Department of Anatomy and K. K. Leung Brain Research Center, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China
| | - Yi Shen
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Yu-Dong Zhou
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China
| | - Min Zhuo
- Center for Neuron and Disease, Frontier Institutes of Life Science, Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jian-Hong Luo
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China.
| | - Tian-Le Xu
- Collaborative Innovation Centre for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xiang-Yao Li
- Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China.
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22
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Integration of innate immune signalling by caspase-8 cleavage of N4BP1. Nature 2020; 587:275-280. [PMID: 32971525 DOI: 10.1038/s41586-020-2796-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
Mutations in the death receptor FAS1,2 or its ligand FASL3 cause autoimmune lymphoproliferative syndrome, whereas mutations in caspase-8 or its adaptor FADD-which mediate cell death downstream of FAS and FASL-cause severe immunodeficiency in addition to autoimmune lymphoproliferative syndrome4-6. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses7-12, but the mechanisms that underlie immunodeficiency remain undefined. Here we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice increased the production of select cytokines upon stimulation of the Toll-like receptor (TLR)1-TLR2 heterodimer (referred to herein as TLR1/2), TLR7 or TLR9, but not upon engagement of TLR3 or TLR4. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages, owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, the impaired production of cytokines in response to TLR3 and TLR4 stimulation of caspase-8-deficient macrophages13 was largely rescued by co-deletion of N4BP1. Thus, the persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumour necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by mutations of FADD and caspase-8.
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23
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Kurmi BD, Patel P, Paliwal R, Paliwal SR. Molecular approaches for targeted drug delivery towards cancer: A concise review with respect to nanotechnology. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101682] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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24
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Savickas S, Kastl P, auf dem Keller U. Combinatorial degradomics: Precision tools to unveil proteolytic processes in biological systems. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140392. [DOI: 10.1016/j.bbapap.2020.140392] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 12/28/2022]
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25
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Zhu Q, Ding L, Zi Z, Gao S, Wang C, Wang Y, Zhu C, Yuan Z, Wei F, Cai Q. Viral-Mediated AURKB Cleavage Promotes Cell Segregation and Tumorigenesis. Cell Rep 2020; 26:3657-3671.e5. [PMID: 30917319 DOI: 10.1016/j.celrep.2019.02.106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 01/04/2019] [Accepted: 02/27/2019] [Indexed: 12/31/2022] Open
Abstract
Aurora kinase B (AURKB), a central regulator of chromosome segregation and cytokinesis, is aberrantly expressed in various cancer cells. However, the relationship of AURKB and oncogenic viruses in cancer progression remains unclear. Here, we reveal that N-cleaved isoforms of AURKB exist in several oncovirus-associated tumor cells and patient cancer tissues, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and human papillomavirus virus (HPV). Mechanistically, in KSHV-infected tumor cells, the latent viral antigen LANA cleaves AURKB at Asp76 in a serine protease-dependent manner. The N'-AURKB relocalizes to the spindle pole and promotes the metaphase-to-telophase transition in mitotic cells. Introduction of N'-AURKB but not C'-AURKB promotes colony formation and malignant growth of tumor cells in vitro and in vivo using a murine xenograft model. Altogether, our findings uncover a proteolytic cleavage mechanism by which oncoviruses induce cancer cell segregation and tumorigenesis.
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Affiliation(s)
- Qing Zhu
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ling Ding
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhenguo Zi
- ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Shujun Gao
- Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chong Wang
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yuyan Wang
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Caixia Zhu
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhenghong Yuan
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Fang Wei
- ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qiliang Cai
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Expert Workstation, Baoji Central Hospital, Baoji, 721008 Shaanxi Province, China.
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26
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Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets. Biomolecules 2020; 10:biom10040612. [PMID: 32326640 PMCID: PMC7225963 DOI: 10.3390/biom10040612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/08/2020] [Accepted: 04/13/2020] [Indexed: 12/27/2022] Open
Abstract
Caspases are proteases conserved throughout Metazoans and responsible for initiating and executing the apoptotic program. Currently, there are over 1800 known apoptotic caspase substrates, many of them known regulators of cell proliferation and death, which makes them attractive therapeutic targets. However, most caspase substrates are by-standers, and identifying novel apoptotic mediators amongst all caspase substrates remains an unmet need. Here, we conducted an in silico search for significant apoptotic caspase targets across different species within the Vertebrata subphylum, using different criteria of conservation combined with structural features of cleavage sites. We observed that P1 aspartate is highly conserved while the cleavage sites are extensively variable and found that cleavage sites are located primarily in coiled regions composed of hydrophilic amino acids. Using the combination of these criteria, we determined the final list of the 107 most relevant caspase substrates including 30 novel targets previously unknown for their role in apoptosis and cancer. These newly identified substrates can be potential regulators of apoptosis and candidates for anti-tumor therapy.
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27
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Ju S, Kwon Y, Kim JM, Park D, Lee S, Lee JW, Hwang CS, Lee C. iNrich, Rapid and Robust Method to Enrich N-Terminal Proteome in a Highly Multiplexed Platform. Anal Chem 2020; 92:6462-6469. [DOI: 10.1021/acs.analchem.9b05653] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Shinyeong Ju
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Yumi Kwon
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Jeong-Mok Kim
- Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Daechan Park
- Department of Biological Sciences, Ajou University, Suwon, Gyeonggi 16499, Republic of Korea
| | - Seonjeong Lee
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Jin-Won Lee
- Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Cheol-Sang Hwang
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Cheolju Lee
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
- Department of Converging Science and Technology, KHU-KIST, Kyung Hee University, Seoul 02447, Republic of Korea
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28
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Corsetti V, Borreca A, Latina V, Giacovazzo G, Pignataro A, Krashia P, Natale F, Cocco S, Rinaudo M, Malerba F, Florio R, Ciarapica R, Coccurello R, D’Amelio M, Ammassari-Teule M, Grassi C, Calissano P, Amadoro G. Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models. Brain Commun 2020; 2:fcaa039. [PMID: 32954296 PMCID: PMC7425324 DOI: 10.1093/braincomms/fcaa039] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/05/2020] [Accepted: 02/12/2020] [Indexed: 12/12/2022] Open
Abstract
Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.
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Affiliation(s)
| | - Antonella Borreca
- Humanitas University Laboratory of Pharmacology and Brain Pathology, Neuro Center, 20089 Milan, Italy
- Institute of Neuroscience, 20129 Milan, Italy
| | | | | | | | - Paraskevi Krashia
- IRCSS Santa Lucia Foundation, 00143 Rome, Italy
- Department of Medicine, University Campus Bio-Medico, 00128 Rome, Italy
- Department of Science and Technology for Humans and Environment, University Campus Bio-medico, 00128 Rome, Italy
| | - Francesca Natale
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Sara Cocco
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Marco Rinaudo
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | | | - Rita Florio
- European Brain Research Institute (EBRI), 00161 Rome, Italy
| | | | - Roberto Coccurello
- IRCSS Santa Lucia Foundation, 00143 Rome, Italy
- Institute for Complex Systems (ISC), CNR, 00185 Rome, Italy
| | - Marcello D’Amelio
- IRCSS Santa Lucia Foundation, 00143 Rome, Italy
- Department of Medicine, University Campus Bio-Medico, 00128 Rome, Italy
- Department of Science and Technology for Humans and Environment, University Campus Bio-medico, 00128 Rome, Italy
| | | | - Claudio Grassi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | | | - Giuseppina Amadoro
- European Brain Research Institute (EBRI), 00161 Rome, Italy
- Institute of Translational Pharmacology (IFT)–National Research Council (CNR), 00133 Rome, Italy
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Yalonetskaya A, Mondragon AA, Hintze ZJ, Holmes S, McCall K. Nuclear degradation dynamics in a nonapoptotic programmed cell death. Cell Death Differ 2020; 27:711-724. [PMID: 31285547 PMCID: PMC7206136 DOI: 10.1038/s41418-019-0382-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 05/28/2019] [Accepted: 06/17/2019] [Indexed: 01/01/2023] Open
Abstract
Nuclear degradation is a major event during programmed cell death (PCD). The breakdown of nuclear components has been well characterized during apoptosis, one form of PCD. Many nonapoptotic forms of PCD have been identified, but our understanding of nuclear degradation during those events is limited. Here, we take advantage of Drosophila oogenesis to investigate nuclear degeneration during stress-induced apoptotic and developmental nonapoptotic cell death in the same cell type in vivo. We find that nuclear Lamin, a caspase substrate, dissociates from the nucleus as an early event during apoptosis, but remains associated with nuclei during nonapoptotic cell death. Lamin reveals a series of changes in nuclear architecture during nonapoptotic death, including nuclear crenellations and involutions. Stretch follicle cells contribute to these architecture changes, and phagocytic and lysosome-associated machinery in stretch follicle cells promote Lamin degradation. More specifically, we find that the lysosomal cathepsin CP1 facilitates Lamin degradation.
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Affiliation(s)
- Alla Yalonetskaya
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA
| | - Albert A Mondragon
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA
- Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA, 02215, USA
| | - Zackary J Hintze
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA
| | - Susan Holmes
- Department of Statistics, Stanford University, Stanford, CA, 94305, USA
| | - Kimberly McCall
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.
- Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston, MA, 02215, USA.
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30
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Chen DY, Husain M. Caspase-Mediated Cleavage of Human Cortactin during Influenza A Virus Infection Occurs in Its Actin-Binding Domains and Is Associated with Released Virus Titres. Viruses 2020; 12:v12010087. [PMID: 31940955 PMCID: PMC7019683 DOI: 10.3390/v12010087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/17/2022] Open
Abstract
Influenza A virus (IAV) exploits host factors to multiply and cause disease. An in-depth knowledge of this interaction of IAV with the host will aid the development of anti-IAV intervention strategies. Previously, we demonstrated that host cortactin, an actin filament-binding protein promotes IAV infection, but undergoes degradation via a lysosome-associated apoptotic pathway during the late stages of IAV infection. Next, we wanted to further understand the mechanisms and significance of this phenomenon. By using the RNA interference screens and site-directed mutagenesis followed by western blotting, we found that lysosome protease, cathepsin C is involved in cortactin degradation in human cells infected with IAV. Furthermore, executioner apoptotic caspase, caspase-3 not caspase-6 or caspase-7 is involved in cortactin degradation during IAV infection, and caspase-3 cleavage site is located in the first actin-binding repeat of cortactin polypeptide. Finally, when expressed ectopically, the cleavage-resistant cortactin mutants decreased the amount of IAV progeny released from infected cells that was enhanced by the cleavage-sensitive cortactin wild type. These data strengthen the hypothesis proposed earlier that host cortactin plays an inhibitory role during the late stages of IAV infection, and IAV is facilitating its degradation to undermine such function.
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Affiliation(s)
| | - Matloob Husain
- Correspondence: ; Tel.: +64-3-470-3420; Fax: +64-3-479-8540
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31
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Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 2019; 20:19-33. [PMID: 30467385 DOI: 10.1038/s41583-018-0093-1] [Citation(s) in RCA: 645] [Impact Index Per Article: 107.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
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Affiliation(s)
- Junying Yuan
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
| | - Palak Amin
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
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32
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Qi E, Wang D, Li Y, Li G, Su Z. Revealing favorable and unfavorable residues in cooperative positions in protease cleavage sites. Biochem Biophys Res Commun 2019; 519:714-720. [PMID: 31543345 DOI: 10.1016/j.bbrc.2019.09.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 09/14/2019] [Indexed: 11/17/2022]
Abstract
Proteases play critical roles in a wide variety of fundamental biological functions, and numerous protease inhibitors have been developed to treat various diseases including cancer. A wide range of experimental and computational methods have been developed to investigate the specificity and catalytic mechanisms of proteases. However, these methods only focused on the preferences of a single position around a cleavage site in a substrate, rarely on the compositionality of the subsites. We present new methods to quantify the specificity of proteases by considering the combinatorial patterns of amino acid residuals of cleavage sites in substrates. By incorporating the preference at positions, we modeled three types of favorable combinations of residues in cleavage sites. Moreover, by constructing a relationship weight matrix of residues between two positions, we can easily identify unfavorable combinations of residues at the positions. Applying these methods to a set of known cleavage sites of proteases, we revealed numerous favorable and unfavorable residues in cooperative positions in the protease cleavage sites. The results can help understand the specificity and catalytic mechanisms of proteases. To our knowledge, this is the first study that quantifies unfavorable combinations of amino acids between two sites. Furthermore, this method is not limited to the study of proteases and cleavage sites, and can be generalized to uncover the relationships of residues at meaningful sites in other proteins.
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Affiliation(s)
- Enfeng Qi
- School of Mathematics, Shandong University, Jinan, 250100, China; School of Mathematics and Statistics, Guangxi Normal University, Guilin, 541000, China
| | - Dongyu Wang
- The State Key Laboratory of Microbial Technology, Shandong University, Jinan, 250100, China
| | - Yang Li
- School of Mathematics, Shandong University, Jinan, 250100, China
| | - Guojun Li
- School of Mathematics, Shandong University, Jinan, 250100, China.
| | - Zhengchang Su
- Department of Bioinformatics and Genomics, The University of North Carolina at Charlotte, Charlotte, 28223, USA.
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Levring TB, Kongsbak-Wismann M, Rode AKO, Al-Jaberi FAH, Lopez DV, Met Ö, Woetmann A, Bonefeld CM, Ødum N, Geisler C. Tumor necrosis factor induces rapid down-regulation of TXNIP in human T cells. Sci Rep 2019; 9:16725. [PMID: 31723203 PMCID: PMC6853882 DOI: 10.1038/s41598-019-53234-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 10/25/2019] [Indexed: 12/19/2022] Open
Abstract
In addition to antigen-driven signals, T cells need co-stimulatory signals for robust activation. Several receptors, including members of the tumor necrosis factor receptor superfamily (TNFRSF), can deliver co-stimulatory signals to T cells. Thioredoxin interacting protein (TXNIP) is an important inhibitor of glucose uptake and cell proliferation, but it is unknown how TXNIP is regulated in T cells. The aim of this study was to determine expression levels and regulation of TXNIP in human T cells. We found that naïve T cells express high levels of TXNIP and that treatment of blood samples with TNF results in rapid down-regulation of TXNIP in the T cells. TNF-induced TXNIP down-regulation correlated with increased glucose uptake. Furthermore, we found that density gradient centrifugation (DGC) induced down-regulation of TXNIP. We demonstrate that DGC induced TNF production that paralleled the TXNIP down-regulation. Treatment of blood with toll-like receptor (TLR) ligands induced TNF production and TXNIP down-regulation, suggesting that damage-associated molecular patterns (DAMPs), such as endogenous TLR ligands, released during DGC play a role in DGC-induced TXNIP down-regulation. Finally, we demonstrate that TNF-induced TXNIP down-regulation is dependent on caspase activity and is caused by caspase-mediated cleavage of TXNIP.
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Affiliation(s)
- Trine B Levring
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martin Kongsbak-Wismann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna K O Rode
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Fatima A H Al-Jaberi
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Daniel V Lopez
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Özcan Met
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Anders Woetmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Ødum
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Apoptotic Fragmentation of Tricellulin. Int J Mol Sci 2019; 20:ijms20194882. [PMID: 31581480 PMCID: PMC6801678 DOI: 10.3390/ijms20194882] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/25/2019] [Accepted: 09/26/2019] [Indexed: 01/02/2023] Open
Abstract
Apoptotic extrusion of cells from epithelial cell layers is of central importance for epithelial homeostasis. As a prerequisite cell-cell contacts between apoptotic cells and their neighbors have to be dissociated. Tricellular tight junctions (tTJs) represent specialized structures that seal polarized epithelial cells at sites where three cells meet and are characterized by the specific expression of tricellulin and angulins. Here, we specifically addressed the fate of tricellulin in apoptotic cells. METHODS Apoptosis was induced by staurosporine or camptothecin in MDCKII and RT-112 cells. The fate of tricellulin was analyzed by Western blotting and immunofluorescence microscopy. Caspase activity was inhibited by Z-VAD-FMK or Z-DEVD-FMK. RESULTS Induction of apoptosis induces the degradation of tricellulin with time. Aspartate residues 487 and 441 were identified as caspase cleavage-sites in the C-terminal coiled-coil domain of human tricellulin. Fragmentation of tricellulin was inhibited in the presence of caspase inhibitors or when Asp487 or Asp441 were mutated to asparagine. Deletion of the tricellulin C-terminal amino acids prevented binding to lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 and thus should impair specific localization of tricellulin to tTJs. CONCLUSIONS Tricellulin is a substrate of caspases and its cleavage in consequence contributes to the dissolution of tTJs during apoptosis.
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35
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Zhu RX, Cheng ASL, Chan HLY, Yang DY, Seto WK. Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis. World J Gastroenterol 2019; 25:4715-4726. [PMID: 31528096 PMCID: PMC6718038 DOI: 10.3748/wjg.v25.i32.4715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/14/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible growth arrest cell cycle, apoptosis, and cell survival. GAS2 protein is universally expressed in most normal tissues, particularly in the liver, but is depleted in some tumor tissues. However, the functional mechanisms of GAS2 in hepatocellular carcinoma (HCC) are not fully defined.
AIM To investigate the function and mechanism of GAS2 in HCC.
METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting. Cell proliferation was analyzed by counting, MTS, and colony formation assays. Cell cycle analysis was performed by flow cytometry. Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.
RESULTS GAS2 protein expression was lower in HCC than in normal tissues. Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53, while knockdown of GAS2 promoted the proliferation of hepatocytes (P < 0.05). Furthermore, GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells, particularly the elevation of sub G1 (P < 0.01). Apoptosis induced by GAS2 was dependent on p53, which was increased by etoposide addition. The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated, but became diminished upon downregulation of GAS2. In the clinic specimen, GAS2 was downregulated in more than 60% of HCCs. The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues (P < 0.05).
CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis, possibly by regulating the cell cycle and p53-dependent apoptosis pathway.
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Affiliation(s)
- Ran-Xu Zhu
- Department of Gastroenterology and Hepatology, The University of Hong Kong–Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Alfred Sze Lok Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Dong-Ye Yang
- Department of Gastroenterology and Hepatology, The University of Hong Kong–Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Wai-Kay Seto
- Department of Gastroenterology and Hepatology, The University of Hong Kong–Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
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36
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Bussaglia E, Antón R, Nomdedéu JF, Fuentes-Prior P. TET2 missense variants in human neoplasia. A proposal of structural and functional classification. Mol Genet Genomic Med 2019; 7:e00772. [PMID: 31187595 PMCID: PMC6625141 DOI: 10.1002/mgg3.772] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 04/02/2019] [Accepted: 04/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background The human TET2 gene plays a pivotal role in the epigenetic regulation of normal and malignant hematopoiesis. Somatic TET2 mutations have been repeatedly identified in age‐related clonal hematopoiesis and in myeloid neoplasms ranging from acute myeloid leukemia (AML) to myeloproliferative neoplasms. However, there have been no attempts to systematically explore the structural and functional consequences of the hundreds of TET2 missense variants reported to date. Methods We have sequenced the TET2 gene in 189 Spanish AML patients using Sanger sequencing and NGS protocols. Next, we performed a thorough bioinformatics analysis of TET2 protein and of the expected impact of all reported TET2 missense variants on protein structure and function, exploiting available structure‐and‐function information as well as 3D structure prediction tools. Results We have identified 38 TET2 allelic variants in the studied patients, including two frequent SNPs: p.G355D (10 cases) and p.I1762V (28 cases). Four of the detected mutations are reported here for the first time: c.122C>T (p.P41L), c.4535C>G (p.A1512G), c.4760A>G (p.D1587G), and c.5087A>T (p.Y1696F). We predict a complex multidomain architecture for the noncatalytic regions of TET2, and in particular the presence of well‐conserved α+β globular domains immediately preceding and following the actual catalytic unit. Further, we provide a rigorous interpretation of over 430 missense SNVs that affect the TET2 catalytic domain, and we hypothesize explanations for ~700 additional variants found within the regulatory regions of the protein. Finally, we propose a systematic classification of all missense mutants and SNPs reported to date into three major categories (severe, moderate, and mild), based on their predicted structural and functional impact. Conclusions The proposed classification of missense TET2 variants would help to assess their clinical impact on human neoplasia and may guide future structure‐and‐function investigations of TET family members.
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Affiliation(s)
- Elena Bussaglia
- Hematology Department and Diagnostic Hematology Group, Barcelona, Spain
| | - Rosa Antón
- Molecular Bases of Disease, The Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Josep F Nomdedéu
- Hematology Department and Diagnostic Hematology Group, Barcelona, Spain
| | - Pablo Fuentes-Prior
- Molecular Bases of Disease, The Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Caspases orchestrate microglia instrumental functions. Prog Neurobiol 2018; 171:50-71. [DOI: 10.1016/j.pneurobio.2018.09.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 09/21/2018] [Accepted: 09/29/2018] [Indexed: 12/16/2022]
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Strigli A, Raab C, Hessler S, Huth T, Schuldt AJT, Alzheimer C, Friedrich T, Burridge PW, Luedde M, Schwake M. Doxorubicin induces caspase-mediated proteolysis of KV7.1. Commun Biol 2018; 1:155. [PMID: 30302399 PMCID: PMC6162258 DOI: 10.1038/s42003-018-0162-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/31/2018] [Indexed: 12/13/2022] Open
Abstract
Kv7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac IKs-channel. Gain- and loss-of-function mutations in KCNQ1 are associated with cardiac arrhthymias, highlighting the importance of modulating IKs activity for cardiac function. Here, we report proteolysis of Kv7.1 as an irreversible posttranslational modification. The identification of two C-terminal fragments of Kv7.1 led us to identify an aspartate critical for the generation of one of the fragments and caspases as responsible for mediating proteolysis. Activating caspases reduces Kv7.1/KCNE1 currents, which is abrogated in cells expressing caspase-resistant channels. Enhanced cleavage of Kv7.1 can be detected for the LQT mutation G460S, which is located adjacent to the cleavage site, whereas a calmodulin-binding-deficient mutation impairs cleavage. Application of apoptotic stimuli or doxorubicin-induced cardiotoxicity provokes caspase-mediated cleavage of endogenous IKs in human cardiomyocytes. In summary, caspases are novel regulatory components of IKs channels that may have important implications for the molecular mechanism of doxorubicin-induced cardiotoxicity. Anne Strigli et al. report that the voltage-gated potassium channel Kv7.1 undergoes caspase-mediated proteolytic cleavage, which reduces its cardiac activity. Their findings implicate caspases as regulators of the IKs channel complex, which may have implications for understanding drug-induced cardiotoxicity.
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Affiliation(s)
- Anne Strigli
- Institute of Biochemistry, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, 24118, Kiel, Germany
| | - Christian Raab
- Institute of Biochemistry, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, 24118, Kiel, Germany
| | - Sabine Hessler
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany
| | - Tobias Huth
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany
| | - Adam J T Schuldt
- Department of Pharmacology and Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Searle Building 8-450, Chicago, IL, 60611, USA
| | - Christian Alzheimer
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany
| | - Thomas Friedrich
- Institut für Chemie PC 14, Technische Universität Berlin, Straße des 17. Juni 135, 10623, Berlin, Germany
| | - Paul W Burridge
- Department of Pharmacology and Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Searle Building 8-450, Chicago, IL, 60611, USA
| | - Mark Luedde
- Department of Internal Medicine III, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany
| | - Michael Schwake
- Institute of Biochemistry, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, 24118, Kiel, Germany. .,Faculty of Chemistry/Biochemistry III, University of Bielefeld, Universitätsstr. 25, 33615, Bielefeld, Germany. .,Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL, 60611-4296, USA.
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Hernández F, Cuadros R, Ollá I, García C, Ferrer I, Perry G, Avila J. Differences in structure and function between human and murine tau. Biochim Biophys Acta Mol Basis Dis 2018; 1865:2024-2030. [PMID: 31189515 DOI: 10.1016/j.bbadis.2018.08.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 08/01/2018] [Accepted: 08/05/2018] [Indexed: 12/18/2022]
Abstract
The main difference between the primary structures of human and mouse tau can be found at the N-terminal end of the protein. Residues 17 to 28 in human tau are not present in the mouse form of the molecule. Here we tested the capacity of these human tau residues to bind to specific proteins. Several proteins were observed to bind to these residues. Among those that showed the greatest binding were three related to energetic processes: enolase, glyceraldehyde 3 phosphate dehydrogenase and creatine kinase B. The latter did not bind to tau from brain extracts taken from patients with Alzheimer's disease (AD). This lack of binding could be due to the modification of CKB by oxidation in AD.
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Affiliation(s)
- Félix Hernández
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Raquel Cuadros
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ivanna Ollá
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Carlos García
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain
| | - Isidre Ferrer
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Department of Pathology and Experimental Therapeutics, University of Barcelona, Service of Pathologic Anatomy, Bellvitge University Hospital, Institute of Neurosciences, Hospitalet de Llobregat, Spain
| | - George Perry
- The University of Texas at San Antonio (UTSA), San Antonio, TX 78249, USA
| | - Jesús Avila
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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Partial Inactivation of the Chromatin Remodelers SMARCA2 and SMARCA4 in Virus-Infected Cells by Caspase-Mediated Cleavage. J Virol 2018; 92:JVI.00343-18. [PMID: 29848589 DOI: 10.1128/jvi.00343-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/22/2018] [Indexed: 01/18/2023] Open
Abstract
The BAF-chromatin remodeling complex, with its mutually exclusive ATPases SMARCA2 and SMARCA4, is essential for the transcriptional activation of numerous genes, including a subset of interferon-stimulated genes (ISGs). Here, we show that C-terminally truncated forms of both SMARCA2 and SMARCA4 accumulate in cells infected with different RNA or DNA viruses. The levels of truncated SMARCA2 or SMARCA4 strongly correlate with the degree of cell damage and death observed after virus infection. The use of a pan-caspase inhibitor and genetically modified cell lines unable to undergo apoptosis revealed that the truncated forms result from the activity of caspases downstream of the activated intrinsic apoptotic pathway. C-terminally cleaved SMARCA2 and SMARCA4 lack potential nuclear localization signals as well as the bromo- and SnAC domain, with the latter two domains believed to be essential for chromatin association and remodeling. Consistent with this belief, C-terminally truncated SMARCA2 was partially relocated to the cytoplasm. However, the remaining nuclear protein was sufficient to induce ISG expression and inhibit the replication of vesicular stomatitis virus and influenza A virus. This suggests that virus-induced apoptosis does not occur at the expense of an intact interferon-mediated antiviral response pathway.IMPORTANCE Efficient induction of interferon-stimulated genes (ISGs) prior to infection is known to effectively convert a cell into an antiviral state, blocking viral replication. Additionally, cells can undergo caspase-mediated apoptosis to control viral infection. Here, we identify SMARCA2 and SMARCA4 to be essential for the efficient induction of ISGs but also to be targeted by cellular caspases downstream of the intrinsic apoptotic pathway. We find that C-terminally cleaved SMARCA2 and SMARCA4 accumulate at late stages of infection, when cell damage already had occurred. Cleavage of the C terminus removes domains important for nuclear localization and chromatin binding of SMARCA2 and SMARCA4. Consequently, the cleaved forms are unable to efficiently accumulate in the cell nucleus. Intriguingly, the remaining nuclear C-terminally truncated SMARCA2 still induced ISG expression, although to lower levels. These data suggest that in virus-infected cells caspase-mediated cell death does not completely inactivate the SMARCA2- and SMARCA4-dependent interferon signaling pathway.
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Zhang K, Lv DW, Li R. B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation. Cell Rep 2018; 21:3445-3457. [PMID: 29262325 DOI: 10.1016/j.celrep.2017.11.071] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 10/21/2017] [Accepted: 11/17/2017] [Indexed: 12/16/2022] Open
Abstract
Epstein-Barr virus (EBV) in tumor cells is predominately in the latent phase, but the virus can undergo lytic reactivation in response to various stimuli. However, the cellular factors that control latency and lytic replication are poorly defined. In this study, we demonstrated that a cellular factor, PIAS1, restricts EBV lytic replication. PIAS1 depletion significantly facilitated EBV reactivation, while PIAS1 reconstitution had the opposite effect. Remarkably, we found that various lytic triggers promote caspase-dependent cleavage of PIAS1 to antagonize PIAS1-mediated restriction and that caspase inhibition suppresses EBV replication through blocking PIAS1 cleavage. We further demonstrated that a cleavage-resistant PIAS1 mutant suppresses EBV replication upon B cell receptor activation. Mechanistically, we demonstrated that PIAS1 acts as an inhibitor for transcription factors involved in lytic gene expression. Collectively, these results establish PIAS1 as a key regulator of EBV lytic replication and uncover a mechanism by which EBV exploits apoptotic caspases to antagonize PIAS1-mediated restriction.
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Affiliation(s)
- Kun Zhang
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Dong-Wen Lv
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Renfeng Li
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
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Al-Jarrah MD, Erekat NS. Parkinson disease-induced upregulation of apoptotic mediators could be attenuated in the skeletal muscle following chronic exercise training. NeuroRehabilitation 2018; 41:823-830. [PMID: 29254117 DOI: 10.3233/nre-172196] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND We have shown elevated levels of p53 and active caspase-3 in gastrocnemius skeletal muscle with Parkinson's disease (PD). The main aim of this study is to examine the impact of endurance exercise training on the expression of p53 and active caspase-3 in the skeletal muscle of mouse with induced Parkinsonism. METHODS Sedentary control (SC), sedentary Parkinson diseased (SPD), and exercised Parkinson diseased (EPD) groups were formed; each consisting of 10 randomly selected normal albino mice. Chronic Parkinson disease was induced in the SPD and EPD animals using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). The expression of p53 and active caspase-3 was investigated, using immunohistochemistry, in the gastrocnemius muscle in each animal group. RESULTS Both p53 and active caspase-3 expression was significantly (p value < 0.05) reduced in the PD gastrocnemius skeletal muscle following endurance exercise training. CONCLUSION Our present data suggest that chronic exercise training reduced Parkinson disease-induced upregulation of p53 and active caspase-3 in gastrocnemius skeletal muscle. Thus, our study suggests that inhibiting p53 and/or active caspase-3 may be considered as a therapeutic approach to ameliorate PD skeletal muscle abnormalities.
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Affiliation(s)
- Muhammed D Al-Jarrah
- Department of Rehabilitation Sciences, Faculty of Applied Medical Sciences, JUST, Irbid, Jordan
| | - Nour S Erekat
- Department of Anatomy, Faculty of Medicine, Jordan University of Science and Technology (JUST), Irbid, Jordan
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Bhagwat SR, Hajela K, Kumar A. Proteolysis to Identify Protease Substrates: Cleave to Decipher. Proteomics 2018; 18:e1800011. [DOI: 10.1002/pmic.201800011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 04/03/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Sonali R. Bhagwat
- Discipline of Biosciences and Biomedical Engineering; Indian Institute of Technology; Indore 453552 Simrol India
| | - Krishnan Hajela
- School of Life Sciences; Devi Ahilya Vishwavidyalaya; Indore 452001 India
| | - Amit Kumar
- Discipline of Biosciences and Biomedical Engineering; Indian Institute of Technology; Indore 453552 Simrol India
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Kumar S, Cieplak P. Effect of phosphorylation and single nucleotide polymorphisms on caspase substrates processing. Apoptosis 2018; 23:194-200. [DOI: 10.1007/s10495-018-1442-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Kaempferol mitigates Endoplasmic Reticulum Stress Induced Cell Death by targeting caspase 3/7. Sci Rep 2018; 8:2189. [PMID: 29391535 PMCID: PMC5794799 DOI: 10.1038/s41598-018-20499-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 01/17/2018] [Indexed: 12/12/2022] Open
Abstract
The Endoplasmic Reticulum (ER) plays a fundamental role in executing multiple cellular processes required for normal cellular function. Accumulation of misfolded/unfolded proteins in the ER triggers ER stress which contributes to progression of multiple diseases including neurodegenerative disorders. Recent reports have shown that ER stress inhibition could provide positive response against neuronal injury, ischemia and obesity in in vivo models. Our search towards finding an ER stress inhibitor has led to the functional discovery of kaempferol, a phytoestrogen possessing ER stress inhibitory activity in cultured mammalian cells. We have shown that kaempferol pre-incubation significantly inhibits the expression of GRP78 (a chaperone) and CHOP (ER stress associated pro-apoptotic transcription factor) under stressed condition. Also, our investigation in the inhibitory specificity of kaempferol has revealed that it inhibits cell death induced by diverse stimuli. Further study on exploring the molecular mechanism implied that kaempferol renders protection by targeting caspases. Both the in silico docking and in vitro assay using recombinant caspase-3 enzyme confirmed the binding of kaempferol to caspases, through an allosteric mode of competitive inhibition. Altogether, we have demonstrated the ability of kaempferol to alleviate ER stress in in vitro model.
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Savickas S, Auf dem Keller U. Targeted degradomics in protein terminomics and protease substrate discovery. Biol Chem 2017; 399:47-54. [PMID: 28850541 DOI: 10.1515/hsz-2017-0187] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 08/21/2017] [Indexed: 02/06/2023]
Abstract
Targeted degradomics integrates positional information into mass spectrometry (MS)-based targeted proteomics workflows and thereby enables analysis of proteolytic cleavage events with unprecedented specificity and sensitivity. Rapid progress in the establishment of protease-substrate relations provides extensive degradomics target lists that now can be tested with help of selected and parallel reaction monitoring (S/PRM) in complex biological systems, where proteases act in physiological environments. In this minireview, we describe the general principles of targeted degradomics, outline the generic experimental workflow of the methodology and highlight recent and future applications in protease research.
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Affiliation(s)
- Simonas Savickas
- Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, CH-8093 Zurich, Switzerland
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Anker Engelunds Vej, Building 301, DK-2800 Kgs. Lyngby, Denmark
| | - Ulrich Auf dem Keller
- Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, CH-8093 Zurich, Switzerland
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Anker Engelunds Vej, Building 301, DK-2800 Kgs. Lyngby, Denmark
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Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential. Int J Mol Sci 2017; 18:ijms18071362. [PMID: 28672880 PMCID: PMC5535855 DOI: 10.3390/ijms18071362] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 12/20/2022] Open
Abstract
The ankyrin repeat domain 1 (ANKRD1) protein is a cardiac-specific stress-response protein that is part of the muscle ankyrin repeat protein family. ANKRD1 is functionally pleiotropic, playing pivotal roles in transcriptional regulation, sarcomere assembly and mechano-sensing in the heart. Importantly, cardiac ANKRD1 has been shown to be highly induced in various cardiomyopathies and in heart failure, although it is still unclear what impact this may have on the pathophysiology of heart failure. This review aims at highlighting the known properties, functions and regulation of ANKRD1, with focus on the underlying mechanisms that may be involved. The current views on the actions of ANKRD1 in cardiovascular disease and its utility as a candidate cardiac biomarker with diagnostic and/or prognostic potential are also discussed. More studies of ANKRD1 are warranted to obtain deeper functional insights into this molecule to allow assessment of its potential clinical applications as a diagnostic or prognostic marker and/or as a possible therapeutic target.
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Caspases and their substrates. Cell Death Differ 2017; 24:1380-1389. [PMID: 28498362 DOI: 10.1038/cdd.2017.44] [Citation(s) in RCA: 566] [Impact Index Per Article: 70.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/21/2017] [Accepted: 02/23/2017] [Indexed: 12/14/2022] Open
Abstract
, or for pyroptosis, gasdermin D. For the most part, it appears that cleavage events function cooperatively in the cell death process to generate a proteolytic synthetic lethal outcome. In contrast to apoptosis, far less is known about caspase biology in non-apoptotic cellular processes, such as cellular remodeling, including which caspases are activated, the mechanisms of their activation and deactivation, and the key substrate targets. Here we survey the progress made in global identification of caspase substrates using proteomics and the exciting new avenues these studies have opened for understanding the molecular logic of substrate cleavage in apoptotic and non-apoptotic processes.
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Chao KL, Kulakova L, Herzberg O. Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein. Proc Natl Acad Sci U S A 2017; 114:E1128-E1137. [PMID: 28154144 PMCID: PMC5321033 DOI: 10.1073/pnas.1616783114] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N- and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88DNVD91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.
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Affiliation(s)
- Kinlin L Chao
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Liudmila Kulakova
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Osnat Herzberg
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850;
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742
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Kumar S, Cieplak P. CaspNeuroD: a knowledgebase of predicted caspase cleavage sites in human proteins related to neurodegenerative diseases. DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION 2016; 2016:baw142. [PMID: 28025335 PMCID: PMC5199200 DOI: 10.1093/database/baw142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/18/2016] [Accepted: 10/06/2016] [Indexed: 12/19/2022]
Abstract
Background: A variety of neurodegenerative diseases (NDs) have been associated with deregulated caspase activation that leads to neuronal death. Caspases appear to be involved in the molecular pathology of NDs by directly cleaving important proteins. For instance, several proteins involved in Alzheimer’s disease, including β-amyloid precursor protein (APP) and presenilins, are known to be cleaved by caspases. Therefore, cell death pathway may play a central role in many neurological diseases, and targeting the important proteins that control the cell survival and death may potentially represent a therapeutic approach for chronic neurodegenerative disorders. Findings: We developed CaspNeuroD, a relational database of in silico predicted caspase cleavage sites in human proteins associated with NDs. The prediction has been done on collection of 249 human proteins reported in clinical studies of NDs using the recently published CaspDB Random Forest machine-learning model. This database could be used for identifying new caspase substrates and further our understanding of the caspase-mediated substrate cleavage in NDs. Conclusion: Our database provides information about potential caspase cleavage sites in a verified set of human proteins involved in NDs. It provides also information about the conservation of cleavage positions in corresponding orthologs, and information about the positions of single nucleotide polymorphisms and posttranslational modifications (PTMs) that may modulate the caspase cleavage efficiency. Database URL:caspdb.sanfordburnham.org/caspneurod.php .
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Affiliation(s)
- Sonu Kumar
- SBP Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Piotr Cieplak
- SBP Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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