|
1
|
Christopoulou ME, Aletras AJ, Papakonstantinou E, Stolz D, Skandalis SS. WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD. Int J Mol Sci 2024; 25:10049. [PMID: 39337534 PMCID: PMC11432718 DOI: 10.3390/ijms251810049] [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: 07/08/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.
Collapse
Affiliation(s)
- Maria-Elpida Christopoulou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Alexios J Aletras
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Eleni Papakonstantinou
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daiana Stolz
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
| |
Collapse
|
|
2
|
Li G, Zhu W, Tian M, Liu R, Ruan Y, Liu C. Genome-Wide Identification of the SPP/SPPL Gene Family and BnaSPPL4 Regulating Male Fertility in Rapeseed ( Brassica napus L.). Int J Mol Sci 2024; 25:3936. [PMID: 38612746 PMCID: PMC11012144 DOI: 10.3390/ijms25073936] [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: 02/27/2024] [Revised: 03/23/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Signal peptide peptidase (SPP) and its homologs, signal peptide peptidase-like (SPPL) proteases, are members of the GxGD-type aspartyl protease family, which is widespread in plants and animals and is a class of transmembrane proteins with significant biological functions. SPP/SPPLs have been identified; however, the functions of SPP/SPPL in rapeseed (Brassica napus L.) have not been reported. In this study, 26 SPP/SPPLs were identified in rapeseed and categorized into three groups: SPP, SPPL2, and SPPL3. These members mainly contained the Peptidase_A22 and PA domains, which were distributed on 17 out of 19 chromosomes. Evolutionary analyses indicated that BnaSPP/SPPLs evolved with a large number of whole-genome duplication (WGD) events and strong purifying selection. Members are widely expressed and play a key role in the growth and development of rapeseed. The regulation of rapeseed pollen fertility by the BnaSPPL4 gene was further validated through experiments based on bioinformatics analysis, concluding that BnaSPPL4 silencing causes male sterility. Cytological observation showed that male infertility caused by loss of BnaSPPL4 gene function occurs late in the mononucleate stage due to microspore dysplasia.
Collapse
Affiliation(s)
- Guangze Li
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| | - Wenjun Zhu
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| | - Minyu Tian
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| | - Rong Liu
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| | - Ying Ruan
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| | - Chunlin Liu
- Yuelushan Laboratory, Hunan Agricultural University, Changsha 410128, China; (G.L.); (W.Z.); (M.T.); (R.L.); (Y.R.)
- Key Laboratory of Hunan Provincial on Crop Epigenetic Regulation and Development, Hunan Agricultural University, Changsha 410128, China
| |
Collapse
|
|
3
|
Mentrup T, Leinung N, Patel M, Fluhrer R, Schröder B. The role of SPP/SPPL intramembrane proteases in membrane protein homeostasis. FEBS J 2024; 291:25-44. [PMID: 37625440 DOI: 10.1111/febs.16941] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/03/2023] [Accepted: 08/23/2023] [Indexed: 08/27/2023]
Abstract
Signal peptide peptidase (SPP) and the four SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 constitute a family of aspartyl intramembrane proteases with homology to presenilins. The different members reside in distinct cellular localisations within the secretory pathway and the endo-lysosomal system. Despite individual cleavage characteristics, they all cleave single-span transmembrane proteins with a type II orientation exhibiting a cytosolic N-terminus. Though the identification of substrates is not complete, SPP/SPPL-mediated proteolysis appears to be rather selective. Therefore, according to our current understanding cleavage by SPP/SPPL proteases rather seems to serve a regulatory function than being a bulk proteolytic pathway. In the present review, we will summarise our state of knowledge on SPP/SPPL proteases and in particular highlight recently identified substrates and the functional and/or (patho)-physiological implications of these cleavage events. Based on this, we aim to provide an overview of the current open questions in the field. These are connected to the regulation of these proteases at the cellular level but also in context of disease and patho-physiological processes. Furthermore, the interplay with other proteostatic systems capable of degrading membrane proteins is beginning to emerge.
Collapse
Affiliation(s)
- Torben Mentrup
- Institute for Physiological Chemistry, Technische Universität Dresden, Germany
| | - Nadja Leinung
- Institute for Physiological Chemistry, Technische Universität Dresden, Germany
| | - Mehul Patel
- Institute for Physiological Chemistry, Technische Universität Dresden, Germany
| | - Regina Fluhrer
- Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Germany
- Center for Interdisciplinary Health Research, University of Augsburg, Germany
| | - Bernd Schröder
- Institute for Physiological Chemistry, Technische Universität Dresden, Germany
| |
Collapse
|
|
4
|
Höppner S, Schröder B, Fluhrer R. Structure and function of SPP/SPPL proteases: insights from biochemical evidence and predictive modeling. FEBS J 2023; 290:5456-5474. [PMID: 37786993 DOI: 10.1111/febs.16968] [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: 05/30/2023] [Revised: 09/13/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase-like (SPPL) proteases have been identified based on their sequence similarity to presenilins, a related family of intramembrane aspartyl proteases. Other than those for the presenilins, no high-resolution structures for the SPP/SPPL proteases are available. Despite this limitation, over the years bioinformatical and biochemical data have accumulated, which altogether have provided a picture of the overall structure and topology of these proteases, their localization in the cell, the process of substrate recognition, their cleavage mechanism, and their function. Recently, the artificial intelligence-based structure prediction tool AlphaFold has added high-confidence models of the expected fold of SPP/SPPL proteases. In this review, we summarize known structural aspects of the SPP/SPPL family as well as their substrates. Of particular interest are the emerging substrate recognition and catalytic mechanisms that might lead to the prediction and identification of more potential substrates and deeper insight into physiological and pathophysiological roles of proteolysis.
Collapse
Affiliation(s)
- Sabine Höppner
- Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Theoretical Medicine, University of Augsburg, Germany
| | - Bernd Schröder
- Institute for Physiological Chemistry, Technische Universität Dresden, Germany
| | - Regina Fluhrer
- Biochemistry and Molecular Biology, Faculty of Medicine, Institute of Theoretical Medicine, University of Augsburg, Germany
- Center for Interdisciplinary Health Research, University of Augsburg, Germany
| |
Collapse
|
|
5
|
Leinung N, Mentrup T, Patel M, Gallagher T, Schröder B. Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains. iScience 2023; 26:107819. [PMID: 37736044 PMCID: PMC10509304 DOI: 10.1016/j.isci.2023.107819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 07/21/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023] Open
Abstract
Signal peptide peptidase-like 2a and b (SPPL2a/b) are aspartyl intramembrane proteases and cleave tail-anchored proteins as well as N-terminal fragments (NTFs) derived from type II-oriented transmembrane proteins. How these proteases recruit substrates and cleavage is regulated, is still incompletely understood. We found that SPPL2a/b localize to detergent-resistant membrane (DRM) domains with the characteristics of tetraspanin-enriched microdomains (TEMs). Based on this, association with several tetraspanins was evaluated. We demonstrate that not only SPPL2a/b but also their substrates tumor necrosis factor (TNF) and CD74 associate with tetraspanins like CD9, CD81, and CD82 and/or TEMs and analyze the stability of these complexes in different detergents. CD9 and CD81 deficiency has protease- and substrate-selective effects on SPPL2a/b function. Our findings suggest that reciprocal interactions with tetraspanins may assist protease-substrate encounters of SPPL2a/b within the membrane. Beyond SPP/SPPL proteases, this supports previous concepts that tetraspanins facilitate membrane-embedded proteolytic processes.
Collapse
Affiliation(s)
- Nadja Leinung
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Torben Mentrup
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Mehul Patel
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Tom Gallagher
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Bernd Schröder
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|
|
6
|
Mentrup T, Stumpff-Niggemann AY, Leinung N, Schlosser C, Schubert K, Wehner R, Tunger A, Schatz V, Neubert P, Gradtke AC, Wolf J, Rose-John S, Saftig P, Dalpke A, Jantsch J, Schmitz M, Fluhrer R, Jacobsen ID, Schröder B. Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis. Nat Commun 2022; 13:1880. [PMID: 35388002 PMCID: PMC8987071 DOI: 10.1038/s41467-022-29474-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/14/2022] [Indexed: 11/23/2022] Open
Abstract
Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses. Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
Collapse
Affiliation(s)
- Torben Mentrup
- Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | | | - Nadja Leinung
- Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Christine Schlosser
- Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Katja Schubert
- Research Group Microbial Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
| | - Rebekka Wehner
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Antje Tunger
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany
| | - Patrick Neubert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany
| | - Ann-Christine Gradtke
- Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Janina Wolf
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Stefan Rose-John
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Paul Saftig
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Alexander Dalpke
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Regina Fluhrer
- Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Ilse D Jacobsen
- Research Group Microbial Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.,Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Bernd Schröder
- Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
| |
Collapse
|
|
7
|
Fukuda Y, Bustos MA, Cho SN, Roszik J, Ryu S, Lopez VM, Burks JK, Lee JE, Grimm EA, Hoon DSB, Ekmekcioglu S. Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient survival in melanoma. Cell Death Dis 2022; 13:117. [PMID: 35121729 PMCID: PMC8816905 DOI: 10.1038/s41419-022-04552-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 12/12/2021] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of sCD74 was observed primarily in melanoma cell lines as well as a THP-1 line of macrophages from monocytes and primary macrophages, especially in response to interferon-γ (IFN-γ). A predominant form that showed clinical relevance was the 25-KDa sCD74, which originated from the 33-KDa isoform of CD74. The release of this sCD74 was regulated by either a disintegrin and metalloproteinase-mediated cell-surface cleavage or cysteine-protease-mediated lysosomal cleavage, depending on cell types. Both recombinant and THP-1 macrophage-released endogenous sCD74 suppressed melanoma cell growth and induced apoptosis under IFN-γ stimulatory conditions via inhibiting the MIF/CD74/AKT-survival pathway. Our findings demonstrate that the interplay between sCD74 and MIF regulates tumor progression and determines patient outcomes in advanced melanoma.
Collapse
Affiliation(s)
- Yasunari Fukuda
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Matias A Bustos
- Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA
| | - Sung-Nam Cho
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jason Roszik
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Suyeon Ryu
- Department of Genome Sequencing, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA
| | - Victor M Lopez
- Department of Genome Sequencing, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA
| | - Jared K Burks
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Elizabeth A Grimm
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Dave S B Hoon
- Department of Genome Sequencing, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA
| | - Suhendan Ekmekcioglu
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| |
Collapse
|
|
8
|
Mentrup T, Schröder B. Signal peptide peptidase-like 2 proteases: Regulatory switches or proteasome of the membrane? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119163. [PMID: 34673079 DOI: 10.1016/j.bbamcr.2021.119163] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 12/30/2022]
Abstract
Signal peptide peptidase-like 2 (SPPL) proteases constitute a subfamily of SPP/SPPL intramembrane proteases which are homologues of the presenilins, the catalytic core of the γ-secretase complex. The three SPPL2 proteases SPPL2a, SPPL2b and SPPL2c proteolyse single-span, type II-oriented transmembrane proteins and/or tail-anchored proteins within their hydrophobic transmembrane segments. We review recent progress in defining substrate spectra and in vivo functions of these proteases. Characterisation of the respective knockout mice has implicated SPPL2 proteases in immune cell differentiation and function, prevention of atherosclerotic plaque development and spermatogenesis. Mechanisms how substrates are selected by these enzymes are still incompletely understood. We will discuss current views on how selective SPPL2-mediated cleavage is or whether these proteases may exhibit a generalised role in the turnover of membrane proteins. This has been suggested previously for the mechanistically related γ-secretase for which the term "proteasome of the membrane" has been coined based on its broad substrate spectrum. With regard to individual substrates, potential signalling functions of the resulting cytosolic cleavage fragments remain a controversial aspect. However, it has been clearly shown that SPPL2 proteases can influence cellular signalling and membrane trafficking by controlling levels of their membrane-bound substrate proteins which highlights these enzymes as regulatory switches. Based on this, regulatory mechanisms controlling activity of SPPL2 proteases would need to be postulated, which are just beginning to emerge. These different questions, which are relevant for other families of intramembrane proteases in a similar way, will be critically discussed based on the current state of knowledge.
Collapse
Affiliation(s)
- Torben Mentrup
- Institute for Physiological Chemistry, Technische Universität Dresden, Fiedlerstraße 42, D-01307 Dresden, Germany
| | - Bernd Schröder
- Institute for Physiological Chemistry, Technische Universität Dresden, Fiedlerstraße 42, D-01307 Dresden, Germany.
| |
Collapse
|
|
9
|
Das J, Banday A, Shandilya J, Sharma M, Vignesh P, Rawat A. An updated review on Mendelian susceptibility to mycobacterial diseases - a silver jubilee celebration of its first genetic diagnosis. Expert Rev Clin Immunol 2021; 17:1103-1120. [PMID: 34259572 DOI: 10.1080/1744666x.2021.1956314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Mendelian susceptibility to mycobacterial diseases (MSMD), a group of at least 18 different genetic disorders, encompasses a specific class of inborn errors of immunity that result in predilection to infection with mycobacteria including the weakly virulent strains. Primarily, these consist of defects in the IFN-γ-IL-12/23 circuit that is crucial for immunity against intracellular microorganisms. Although the first genetic etiology of MSMD was discovered in 1996, molecular diagnosis of MSMD in resource-constrained settings may remain far-fetched. Recently, original studies have emerged from developing countries, including India, wherein the genetic diagnosis was confirmed within the country itself. A lag of about 25 years, hence, seems to exist. AREAS COVERED Herein, we review the clinical, laboratory, and mutational profile of the genetic defects responsible for causing MSMD. We intend to enhance the recognition of these disorders in settings endemic for tuberculosis and bridge the gap between the developed and developing countries in the field of MSMD research and therapeutics. EXPERT OPINION Research in the field of MSMD in developing countries, including India, can uncover novel genetic etiologies, as the population exceeds 1.3 billion, a huge burden of tuberculosis (across all clinical spectrums) exists, and BCG vaccination is given universally at birth.
Collapse
Affiliation(s)
- Jhumki Das
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Aaqib Banday
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Jitendra Shandilya
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Madhubala Sharma
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Pandiarajan Vignesh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| |
Collapse
|
|
10
|
Gradtke AC, Mentrup T, Lehmann CHK, Cabrera-Cabrera F, Desel C, Okakpu D, Assmann M, Dalpke A, Schaible UE, Dudziak D, Schröder B. Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2021; 206:164-180. [PMID: 33239420 DOI: 10.4049/jimmunol.2000151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 10/30/2020] [Indexed: 12/30/2022]
Abstract
Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.
Collapse
Affiliation(s)
- Ann-Christine Gradtke
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Torben Mentrup
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Christian H K Lehmann
- Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, D-91052 Erlangen, Germany.,Medical Immunology Campus Erlangen, D-91054 Erlangen, Germany.,Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany.,Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg, D-91054 Erlangen, Germany
| | - Florencia Cabrera-Cabrera
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany.,Biochemical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany
| | - Christine Desel
- Biochemical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany
| | - Darian Okakpu
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Maike Assmann
- Priority Program Infections, Division of Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, and German Center for Infection Research, partner site Borstel, D-23845 Borstel, Germany; and
| | - Alexander Dalpke
- Institute of Medical Microbiology and Hygiene, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Ulrich E Schaible
- Priority Program Infections, Division of Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, and German Center for Infection Research, partner site Borstel, D-23845 Borstel, Germany; and
| | - Diana Dudziak
- Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, D-91052 Erlangen, Germany.,Medical Immunology Campus Erlangen, D-91054 Erlangen, Germany.,Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany.,Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg, D-91054 Erlangen, Germany
| | - Bernd Schröder
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany;
| |
Collapse
|
|
11
|
Papadopoulou AA, Fluhrer R. Signaling Functions of Intramembrane Aspartyl-Proteases. Front Cardiovasc Med 2020; 7:591787. [PMID: 33381526 PMCID: PMC7768045 DOI: 10.3389/fcvm.2020.591787] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/16/2020] [Indexed: 01/18/2023] Open
Abstract
Intramembrane proteolysis is more than a mechanism to "clean" the membranes from proteins no longer needed. By non-reversibly modifying transmembrane proteins, intramembrane cleaving proteases hold key roles in multiple signaling pathways and often distinguish physiological from pathological conditions. Signal peptide peptidase (SPP) and signal peptide peptidase-like proteases (SPPLs) recently have been associated with multiple functions in the field of signal transduction. SPP/SPPLs together with presenilins (PSs) are the only two families of intramembrane cleaving aspartyl proteases known in mammals. PS1 or PS2 comprise the catalytic center of the γ-secretase complex, which is well-studied in the context of Alzheimer's disease. The mammalian SPP/SPPL family of intramembrane cleaving proteases consists of five members: SPP and its homologous proteins SPPL2a, SPPL2b, SPPL2c, and SPPL3. Although these proteases were discovered due to their homology to PSs, it became evident in the past two decades that no physiological functions are shared between these two families. Based on studies in cell culture models various substrates of SPP/SPPL proteases have been identified in the past years and recently-developed mouse lines lacking individual members of this protease family, will help to further clarify the physiological functions of these proteases. In this review we concentrate on signaling roles of mammalian intramembrane cleaving aspartyl proteases. In particular, we will highlight the signaling roles of PS via its substrates NOTCH, VEGF, and others, mainly focusing on its involvement in vasculature. Delineating also signaling pathways that are affected and/or controlled by SPP/SPPL proteases. From SPP's participation in tumor progression and survival, to SPPL3's regulation of protein glycosylation and SPPL2c's control over cellular calcium stores, various crossovers between proteolytic activity of intramembrane proteases and cell signaling will be described.
Collapse
Affiliation(s)
- Alkmini A. Papadopoulou
- Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Regina Fluhrer
- Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| |
Collapse
|
|
12
|
Pouille CL, Jegou D, Dugardin C, Cudennec B, Ravallec R, Hance P, Rambaud C, Hilbert JL, Lucau-Danila A. Chicory root flour – A functional food with potential multiple health benefits evaluated in a mice model. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
|
|
13
|
Talele TT. Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon. J Med Chem 2020; 63:13291-13315. [PMID: 32805118 DOI: 10.1021/acs.jmedchem.0c00829] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effective and selective binding to target proteins compared to planar compounds with a high sp2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp3-rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.
Collapse
Affiliation(s)
- Tanaji T Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States
| |
Collapse
|
|
14
|
Signal Peptide Peptidase-Type Proteases: Versatile Regulators with Functions Ranging from Limited Proteolysis to Protein Degradation. J Mol Biol 2020; 432:5063-5078. [DOI: 10.1016/j.jmb.2020.05.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/02/2020] [Accepted: 05/19/2020] [Indexed: 12/15/2022]
|
|
15
|
Mentrup T, Cabrera-Cabrera F, Fluhrer R, Schröder B. Physiological functions of SPP/SPPL intramembrane proteases. Cell Mol Life Sci 2020; 77:2959-2979. [PMID: 32052089 PMCID: PMC7366577 DOI: 10.1007/s00018-020-03470-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/09/2020] [Accepted: 01/22/2020] [Indexed: 01/07/2023]
Abstract
Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.
Collapse
Affiliation(s)
- Torben Mentrup
- Institute for Physiological Chemistry, Medizinisch-Theoretisches Zentrum MTZ, Technische Universität Dresden, Fiedlerstraße 42, 01307, Dresden, Germany
| | - Florencia Cabrera-Cabrera
- Institute for Physiological Chemistry, Medizinisch-Theoretisches Zentrum MTZ, Technische Universität Dresden, Fiedlerstraße 42, 01307, Dresden, Germany
| | - Regina Fluhrer
- Biochemistry and Molecular Biology, Faculty of Medicine, University of Augsburg, Universitätsstraße 2, 86135, Augsburg, Germany
- Biomedizinisches Centrum (BMC), Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 17, 81377, Munich, Germany
- DZNE-German Center for Neurodegenerative Diseases, Munich, Feodor-Lynen-Strasse 17, 81377, Munich, Germany
| | - Bernd Schröder
- Institute for Physiological Chemistry, Medizinisch-Theoretisches Zentrum MTZ, Technische Universität Dresden, Fiedlerstraße 42, 01307, Dresden, Germany.
| |
Collapse
|
|
16
|
van Kempen TS, Leijten EFA, Lindenbergh MFS, Nordkamp MO, Driessen C, Lebbink RJ, Baerlecken N, Witte T, Radstake TRDJ, Boes M. Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti-CD74 autoantibodies in human ankylosing spondylitis. Eur J Immunol 2020; 50:1209-1219. [PMID: 32198923 PMCID: PMC7496470 DOI: 10.1002/eji.201948502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/10/2020] [Indexed: 12/14/2022]
Abstract
Ankylosing spondylitis (AS) is associated with autoantibody production to class II MHC‐associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti‐CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase‐like 2A (SPPL2a). We analyzed monocytes from healthy controls (n = 42), psoriatic arthritis (n = 25), rheumatoid arthritis (n = 16), and AS patients (n = 15) for SPPL2a enzyme activity and complemented the experiments using SPPL2a‐sufficient and ‐deficient THP‐1 cells. We found defects in SPPL2a function and CD74 processing in a subset of AS patients, which culminated in CD74 and HLA class II display at the cell surface. These findings were verified in SPPL2a‐deficient THP‐1 cells, which showed expedited expression of MHC class II, total CD74 and CD74 N‐terminal degradation products at the plasma membrane upon receipt of an inflammatory trigger. Furthermore, we observed that IgG anti‐CD74/CLIP autoantibodies recognize CD74 N‐terminal degradation products that accumulate upon SPPL2a defect. In conclusion, reduced activity of SPPL2a protease in monocytes from AS predisposes to endosomal accumulation of CD74 and CD74 N‐terminal fragments, which, upon IFN‐γ‐exposure, is deposited at the plasma membrane and can be recognized by anti‐CD74/CLIP autoantibodies.
Collapse
Affiliation(s)
- Tessa S van Kempen
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Emmerik F A Leijten
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marthe F S Lindenbergh
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Michel Olde Nordkamp
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Christoph Driessen
- Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Robert-Jan Lebbink
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Niklas Baerlecken
- Department of Clinical Immunology and Rheumatology, Medical University Hannover, Hannover, Germany
| | - Torsten Witte
- Department of Clinical Immunology and Rheumatology, Medical University Hannover, Hannover, Germany
| | - Timothy R D J Radstake
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marianne Boes
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands
| |
Collapse
|
|
17
|
Kupke T, Klare JP, Brügger B. Heme binding of transmembrane signaling proteins undergoing regulated intramembrane proteolysis. Commun Biol 2020; 3:73. [PMID: 32060393 PMCID: PMC7021776 DOI: 10.1038/s42003-020-0800-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 01/29/2020] [Indexed: 12/18/2022] Open
Abstract
Transmembrane signaling proteins play a crucial role in the transduction of information across cell membranes. One function of regulated intramembrane proteolysis (RIP) is the release of signaling factors from transmembrane proteins. To study the role of transmembrane domains (TMDs) in modulating structure and activity of released signaling factors, we purified heterologously expressed human transmembrane proteins and their proteolytic processing products from Escherichia coli. Here we show that CD74 and TNFα are heme binding proteins. Heme coordination depends on both a cysteine residue proximal to the membrane and on the oligomerization of the TMD. Furthermore, we show that the various processing products have different modes of heme coordination. We suggest that RIP changes the mode of heme binding of these proteins and generates heme binding peptides with yet unexplored functions. The identification of a RIP modulated cofactor binding of transmembrane signaling proteins sheds new light on the regulation of cell signaling pathways. Kupke et al. study regulated intramembrane proteolysis (RIP) using recombinant transmembrane proteins CD74 and TNFα and find they are heme binding proteins that change their mode of heme binding after proteolytic processing. These data suggest that RIP of type II transmembrane proteins can generate intracellular heme sensor peptides.
Collapse
Affiliation(s)
- Thomas Kupke
- Heidelberg University Biochemistry Center, Heidelberg, Germany.
| | - Johann P Klare
- Department of Physics, University of Osnabrück, Osnabrück, Germany
| | - Britta Brügger
- Heidelberg University Biochemistry Center, Heidelberg, Germany.
| |
Collapse
|
|
18
|
Bustamante J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet 2020; 139:993-1000. [PMID: 32025907 DOI: 10.1007/s00439-020-02120-y] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 01/18/2020] [Indexed: 02/06/2023]
Abstract
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Affected patients are highly and selectively susceptible to weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines. Since 1996, disease-causing mutations have been reported in 15 genes, with allelic heterogeneity leading to 30 genetic disorders. Here, we briefly review the progress made in molecular, cellular, immunological, and clinical studies of MSMD since the last review published in 2018. Highlights include the discoveries of new genetic etiologies of MSMD: autosomal recessive (AR) complete deficiencies of (1) SPPL2a, (2) IL-12Rβ2, and (3) IL-23R, and (4) homozygosity for TYK2 P1104A, resulting in selective impairment of responses to IL-23. The penetrance of SPPL2a deficiency for MSMD is high, probably complete, whereas that of IL-12Rβ2 and IL-23R deficiencies, and TYK2 P1104A homozygosity, is incomplete, and probably low. SPPL2a deficiency has added weight to the notion that human cDC2 and Th1* cells are important for antimycobacterial immunity. Studies of IL-12Rβ2 and IL-23R deficiencies, and of homozygosity for P1104A TYK2, have shown that both IL-12 and IL-23 are required for optimal levels of IFN-γ. These recent findings illustrate how forward genetic studies of MSMD are continuing to shed light on the mechanisms of protective immunity to mycobacteria in humans.
Collapse
Affiliation(s)
- Jacinta Bustamante
- Imagine Institute, Paris University, Paris, France. .,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France. .,Study Center for Primary Immunodeficiencies, AP-HP, Necker Children Hospital, Paris, France.
| |
Collapse
|
|
19
|
Alzheimer’s Disease Genetics: Review of Novel Loci Associated with Disease. CURRENT GENETIC MEDICINE REPORTS 2020. [DOI: 10.1007/s40142-020-00182-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
20
|
Beard HA, Barniol-Xicota M, Yang J, Verhelst SHL. Discovery of Cellular Roles of Intramembrane Proteases. ACS Chem Biol 2019; 14:2372-2388. [PMID: 31287658 DOI: 10.1021/acschembio.9b00404] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intramembrane proteases (IMPs) are localized within lipid bilayers of membranes-either the cell membrane or membranes of various organelles. Cleavage of substrates often results in release from the membrane, leading to a downstream biological effect. This mechanism allows different signaling events to happen through intramembrane proteolysis. Over the years, various mechanistically distinct families of IMPs have been discovered, but the research progress has generally been slower than for soluble proteases due to the challenges associated with membrane proteins. In this review we summarize how each mechanistic family of IMPs was discovered, which chemical tools are available for the study of IMPs, and which techniques have been developed for the discovery of IMP substrates. Finally, we discuss the various roles in cellular physiology of some of these IMPs.
Collapse
Affiliation(s)
- Hester A. Beard
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Marta Barniol-Xicota
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Jian Yang
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Steven H. L. Verhelst
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
- Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany
| |
Collapse
|
|
21
|
Kühnle N, Dederer V, Lemberg MK. Intramembrane proteolysis at a glance: from signalling to protein degradation. J Cell Sci 2019; 132:132/16/jcs217745. [DOI: 10.1242/jcs.217745] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
ABSTRACT
Over the last two decades, a group of unusual proteases, so-called intramembrane proteases, have become increasingly recognized for their unique ability to cleave peptide bonds within cellular membranes. They are found in all kingdoms of life and fulfil versatile functions ranging from protein maturation, to activation of signalling molecules, to protein degradation. In this Cell Science at a Glance article and the accompanying poster, we focus on intramembrane proteases in mammalian cells. By comparing intramembrane proteases in different cellular organelles, we set out to review their functions within the context of the roles of individual cellular compartments. Additionally, we exemplify their mode of action in relation to known substrates by distinguishing cleavage events that promote degradation of substrate from those that release active domains from the membrane bilayer.
Collapse
Affiliation(s)
- Nathalie Kühnle
- Centre for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
| | - Verena Dederer
- Centre for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
| | - Marius K. Lemberg
- Centre for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
| |
Collapse
|
|
22
|
Velcicky J, Mathison CJN, Nikulin V, Pflieger D, Epple R, Azimioara M, Cow C, Michellys PY, Rigollier P, Beisner DR, Bodendorf U, Guerini D, Liu B, Wen B, Zaharevitz S, Brandl T. Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors. ACS Med Chem Lett 2019; 10:887-892. [PMID: 31223443 DOI: 10.1021/acsmedchemlett.9b00044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/16/2019] [Indexed: 01/12/2023] Open
Abstract
SPPL2a (Signal Peptide Peptidase Like 2a) is an intramembrane aspartyl protease engaged in the function of B-cells and dendritic cells. Despite being an attractive target for modulation of the immune system, selective SPPL2a inhibitors are barely described in the literature. Recently, we have disclosed a selective, small molecular weight agent SPL-707 which confirmed that pharmacological inhibition of SPPL2a leads to the accumulation of its substrate CD74/p8 and as a consequence to a reduction in the number of B-cells as well as myeloid dendritic cells in mice. In this paper we describe the discovery of novel hydroxyethylamine based SPPL2a inhibitors. Starting from a rather lipophilic screening hit, several iterative optimization cycles allowed for its transformation into a highly potent and selective compound 15 (SPL-410) which inhibited in vivo CD74/p8 fragment processing in mice at 10 mg/kg oral dose.
Collapse
Affiliation(s)
| | - Casey J. N. Mathison
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Victor Nikulin
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | | - Robert Epple
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Mihai Azimioara
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Christopher Cow
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Pierre-Yves Michellys
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | | - Daniel R. Beisner
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | | | | - Bo Liu
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Ben Wen
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Samantha Zaharevitz
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | |
Collapse
|
|
23
|
Kang I, Bucala R. The immunobiology of MIF: function, genetics and prospects for precision medicine. Nat Rev Rheumatol 2019; 15:427-437. [DOI: 10.1038/s41584-019-0238-2] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2019] [Indexed: 01/01/2023]
|
|
24
|
Martínez-Barricarte R, Kong XF, Casanova JL. Measurement of CD74 N-terminal Fragment Accumulation in Cells Treated with SPPL2a Inhibitor. Bio Protoc 2019; 9:e3254. [PMID: 33654779 DOI: 10.21769/bioprotoc.3254] [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: 02/11/2019] [Revised: 04/29/2019] [Accepted: 05/27/2019] [Indexed: 11/02/2022] Open
Abstract
The recent discovery of human signal peptide peptidase-like 2a (SPPL2a) deficiency in humans revealed the toxicity associated with the accumulation of one of its substrates, CD74 N-terminal fragment (CD74-NTF), for certain type of dendritic cells (cDC2). We developed a two-step protocol for monitoring the accumulation of this molecule in different subsets of PBMCs and immortalized B cells, in which SPPL2a is chemically inhibited and CD74-NTF levels are then assessed by flow cytometry or western blotting. The chemical inhibition of SPPL2a has been described elsewhere, but this is the first time that this inhibition has been reported as a protocol.
Collapse
Affiliation(s)
- Rubén Martínez-Barricarte
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York City, NY, USA
| | - Xiao-Fei Kong
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York City, NY, USA
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York City, NY, USA.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France.,Howard Hughes Medical Institute, New York, USA.,Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| |
Collapse
|
|
25
|
Jankauskas SS, Wong DW, Bucala R, Djudjaj S, Boor P. Evolving complexity of MIF signaling. Cell Signal 2019; 57:76-88. [DOI: 10.1016/j.cellsig.2019.01.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 01/27/2023]
|
|
26
|
Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N, Markle J, Okada S, Boisson-Dupuis S, Casanova JL, Bustamante J. Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunol Cell Biol 2019; 97:360-367. [PMID: 30264912 PMCID: PMC6438774 DOI: 10.1111/imcb.12210] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/20/2018] [Accepted: 09/24/2018] [Indexed: 12/13/2022]
Abstract
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.
Collapse
Affiliation(s)
- Jérémie Rosain
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France, EU
- Paris Descartes University, Imagine Institute, Paris, France, EU
- Study Center for Primary Immunodeficiencies, AP-HP, Necker Children Hospital, Paris, France, EU
| | - Xiao-Fei Kong
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Ruben Martinez-Barricarte
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Carmen Oleaga-Quintas
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France, EU
- Paris Descartes University, Imagine Institute, Paris, France, EU
| | - Noé Ramirez-Alejo
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Janet Markle
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Satoshi Okada
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France, EU
- Paris Descartes University, Imagine Institute, Paris, France, EU
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France, EU
- Paris Descartes University, Imagine Institute, Paris, France, EU
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France, EU
- Howard Hughes Medical Institute, New York, NY, USA
| | - Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France, EU
- Paris Descartes University, Imagine Institute, Paris, France, EU
- Study Center for Primary Immunodeficiencies, AP-HP, Necker Children Hospital, Paris, France, EU
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| |
Collapse
|
|
27
|
Niemeyer J, Mentrup T, Heidasch R, Müller SA, Biswas U, Meyer R, Papadopoulou AA, Dederer V, Haug-Kröper M, Adamski V, Lüllmann-Rauch R, Bergmann M, Mayerhofer A, Saftig P, Wennemuth G, Jessberger R, Fluhrer R, Lichtenthaler SF, Lemberg MK, Schröder B. The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. EMBO Rep 2019; 20:e46449. [PMID: 30733280 PMCID: PMC6399600 DOI: 10.15252/embr.201846449] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 11/09/2022] Open
Abstract
Signal peptide peptidase (SPP) and the four homologous SPP-like (SPPL) proteases constitute a family of intramembrane aspartyl proteases with selectivity for type II-oriented transmembrane segments. Here, we analyse the physiological function of the orphan protease SPPL2c, previously considered to represent a non-expressed pseudogene. We demonstrate proteolytic activity of SPPL2c towards selected tail-anchored proteins. Despite shared ER localisation, SPPL2c and SPP exhibit distinct, though partially overlapping substrate spectra and inhibitory profiles, and are organised in different high molecular weight complexes. Interestingly, SPPL2c is specifically expressed in murine and human testis where it is primarily localised in spermatids. In mice, SPPL2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, but preserved fertility. However, matings of male and female SPPL2c-/- mice exhibit reduced litter sizes. Using proteomics we identify the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2)-regulating protein phospholamban (PLN) as a physiological SPPL2c substrate. Accumulation of PLN correlates with a decrease in intracellular Ca2+ levels in elongated spermatids that likely contribute to the compromised male germ cell differentiation and function of SPPL2c-/- mice.
Collapse
Affiliation(s)
- Johannes Niemeyer
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Torben Mentrup
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Ronny Heidasch
- Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
| | - Stephan A Müller
- DZNE - German Center for Neurodegenerative Diseases, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich, Munich, Germany
| | - Uddipta Biswas
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Rieke Meyer
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Alkmini A Papadopoulou
- Institute for Metabolic Biochemistry, Biomedical Center (BMC) München, Ludwig Maximilians University of Munich, Munich, Germany
| | - Verena Dederer
- Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
| | - Martina Haug-Kröper
- Institute for Metabolic Biochemistry, Biomedical Center (BMC) München, Ludwig Maximilians University of Munich, Munich, Germany
| | - Vivian Adamski
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Martin Bergmann
- Institute of Veterinary Anatomy, Justus Liebig University of Gießen, Gießen, Germany
| | - Artur Mayerhofer
- Cell Biology, Anatomy III, Biomedical Center (BMC) München, Ludwig Maximilians University of Munich, Munich, Germany
| | - Paul Saftig
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Gunther Wennemuth
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
| | - Rolf Jessberger
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Regina Fluhrer
- DZNE - German Center for Neurodegenerative Diseases, Munich, Germany
- Institute for Metabolic Biochemistry, Biomedical Center (BMC) München, Ludwig Maximilians University of Munich, Munich, Germany
| | - Stefan F Lichtenthaler
- DZNE - German Center for Neurodegenerative Diseases, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Marius K Lemberg
- Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Heidelberg, Germany
| | - Bernd Schröder
- Biochemical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|
|
28
|
Mentrup T, Theodorou K, Cabrera-Cabrera F, Helbig AO, Happ K, Gijbels M, Gradtke AC, Rabe B, Fukumori A, Steiner H, Tholey A, Fluhrer R, Donners M, Schröder B. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. J Exp Med 2019; 216:807-830. [PMID: 30819724 PMCID: PMC6446863 DOI: 10.1084/jem.20171438] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 08/21/2018] [Accepted: 10/17/2018] [Indexed: 11/27/2022] Open
Abstract
The intramembrane proteases SPPL2a/b control pro-atherogenic signaling of membrane-bound proteolytic fragments derived from the oxLDL receptor LOX-1. In mice deficient for these proteases, plaque development and fibrosis is enhanced. This highlights SPPL2a/b as crucial players of a novel athero-protective mechanism, which is conserved in humans. The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1–mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase–like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.
Collapse
Affiliation(s)
- Torben Mentrup
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.,Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| | - Kosta Theodorou
- Department of Pathology, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands
| | - Florencia Cabrera-Cabrera
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.,Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| | - Andreas O Helbig
- Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany
| | - Kathrin Happ
- Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| | - Marion Gijbels
- Department of Pathology, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands.,Department of Molecular Genetics, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands.,Amsterdam Cardiovascular Sciences, Department of Medical Biochemistry, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Ann-Christine Gradtke
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.,Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| | - Björn Rabe
- Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| | - Akio Fukumori
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Harald Steiner
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Biomedical Center, Metabolic Biochemistry, Ludwig Maximilians University of Munich, Munich, Germany
| | - Andreas Tholey
- Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany
| | - Regina Fluhrer
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Biomedical Center, Metabolic Biochemistry, Ludwig Maximilians University of Munich, Munich, Germany
| | - Marjo Donners
- Department of Pathology, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands
| | - Bernd Schröder
- Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany .,Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
| |
Collapse
|
|
29
|
Rey-Jurado E, Pizarro-Ortega MS, Kalergis AM. Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease. Cell Mol Immunol 2018; 15:1091-1094. [PMID: 30405151 DOI: 10.1038/s41423-018-0177-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 10/13/2018] [Indexed: 11/09/2022] Open
Affiliation(s)
- Emma Rey-Jurado
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile
| | - Magdalena S Pizarro-Ortega
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile. .,Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile.
| |
Collapse
|
|
30
|
Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T, Deenick EK, Ma CS, Breton G, Lucero KB, Langlais D, Bousfiha A, Aytekin C, Markle J, Trouillet C, Jabot-Hanin F, Arlehamn CSL, Rao G, Picard C, Lasseau T, Latorre D, Hambleton S, Deswarte C, Itan Y, Abarca K, Moraes-Vasconcelos D, Ailal F, Ikinciogullari A, Dogu F, Benhsaien I, Sette A, Abel L, Boisson-Dupuis S, Schröder B, Nussenzweig MC, Liu K, Geissmann F, Tangye SG, Gros P, Sallusto F, Bustamante J, Casanova JL. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol 2018; 19:973-985. [PMID: 30127434 PMCID: PMC6130844 DOI: 10.1038/s41590-018-0178-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 07/02/2018] [Indexed: 12/21/2022]
Abstract
Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.
Collapse
Affiliation(s)
- Xiao-Fei Kong
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
| | - Ruben Martinez-Barricarte
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
| | - James Kennedy
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Federico Mele
- Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland, Bellinzona, Switzerland
| | - Tomi Lazarov
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York , NY, USA
| | - Elissa K Deenick
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia
| | - Cindy S Ma
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia
| | - Gaëlle Breton
- Laboratory of Molecular Immunology, The Rockefeller University, New York , NY, USA
| | - Kimberly B Lucero
- Department of Microbiology and Immunology, Columbia University Medical Center, New York , NY, USA
| | - David Langlais
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Aziz Bousfiha
- Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco
- Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, Casablanca, Morocco
| | - Caner Aytekin
- Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Janet Markle
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
| | - Céline Trouillet
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York , NY, USA
| | - Fabienne Jabot-Hanin
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | | | - Geetha Rao
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia
| | - Capucine Picard
- Paris Descartes University, Imagine Institute, Paris, France
- Study Center for Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France
- Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Théo Lasseau
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
| | - Daniela Latorre
- Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland, Bellinzona, Switzerland
| | - Sophie Hambleton
- Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Caroline Deswarte
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Yuval Itan
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
| | - Katia Abarca
- Department of Pediatric Infectious Diseases and Immunology, Millennium Institute of Immunology and Immunotherapy, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile
| | - Dewton Moraes-Vasconcelos
- Laboratory of Investigation in Dermatology and Immunodeficiencies, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Fatima Ailal
- Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco
- Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, Casablanca, Morocco
| | - Aydan Ikinciogullari
- Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - Figen Dogu
- Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - Ibtihal Benhsaien
- Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco
- Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, Casablanca, Morocco
| | - Alessandro Sette
- La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Stéphanie Boisson-Dupuis
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Bernd Schröder
- Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany
- Institute of Physiological Chemistry, Technical University Dresden, Dresden, Germany
| | - Michel C Nussenzweig
- Laboratory of Molecular Immunology, The Rockefeller University, New York , NY, USA
- Howard Hughes Medical Institute, New York, NY, USA
| | - Kang Liu
- Department of Microbiology and Immunology, Columbia University Medical Center, New York , NY, USA
| | - Frédéric Geissmann
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York , NY, USA
| | - Stuart G Tangye
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia
| | - Philippe Gros
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Federica Sallusto
- Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland, Bellinzona, Switzerland
- Institute of Microbiology, ETH Zurich, Zürich, Switzerland
| | - Jacinta Bustamante
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
- Study Center for Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA.
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
- Paris Descartes University, Imagine Institute, Paris, France.
- Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
- Howard Hughes Medical Institute, New York, NY, USA.
| |
Collapse
|
|
31
|
Abstract
In the current issue of Nature Immunology , Casanova and colleagues demonstrate that humans (and mouse models) with autosomal-recessive SPPL2a deficiency have a severe defect in conventional dendritic cell 2 survival and production of IL-12 and IL-23, and diminished IFN-γ secretion by mycobacterium-specific memory T cells, thus resulting in increased susceptibility to mycobacterial diseases.
Collapse
Affiliation(s)
- Sergio D Rosenzweig
- Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA.
| |
Collapse
|
|
32
|
Lichtenthaler SF, Lemberg MK, Fluhrer R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J 2018; 37:e99456. [PMID: 29976761 PMCID: PMC6068445 DOI: 10.15252/embj.201899456] [Citation(s) in RCA: 207] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/05/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.
Collapse
Affiliation(s)
- Stefan F Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Neuroproteomics, Klinikum rechts der Isar, School of Medicine, and Institute for Advanced Study, Technical University Munich, Munich, Germany
- Munich Center for Systems Neurology (SyNergy), Munich, Germany
| | - Marius K Lemberg
- Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Regina Fluhrer
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Biomedizinisches Centrum (BMC), Ludwig-Maximilians University of Munich, Munich, Germany
| |
Collapse
|
|
33
|
Ran Y, Hossain F, Pannuti A, Lessard CB, Ladd GZ, Jung JI, Minter LM, Osborne BA, Miele L, Golde TE. γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 2018; 9:950-966. [PMID: 28539479 PMCID: PMC5494507 DOI: 10.15252/emmm.201607265] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
γ-Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Extending these findings to mammosphere inhibition assays in triple-negative breast cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ-secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of γ-secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ-secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds.
Collapse
Affiliation(s)
- Yong Ran
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Fokhrul Hossain
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Antonio Pannuti
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Christian B Lessard
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Gabriela Z Ladd
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Joo In Jung
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Lisa M Minter
- Department of Veterinary and Animal Sciences and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA
| | - Barbara A Osborne
- Department of Veterinary and Animal Sciences and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA
| | - Lucio Miele
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Todd E Golde
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
34
|
Velcicky J, Bodendorf U, Rigollier P, Epple R, Beisner DR, Guerini D, Smith P, Liu B, Feifel R, Wipfli P, Aichholz R, Couttet P, Dix I, Widmer T, Wen B, Brandl T. Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo. J Med Chem 2018; 61:865-880. [DOI: 10.1021/acs.jmedchem.7b01371] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
| | | | | | - Robert Epple
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Daniel R. Beisner
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | | | | - Bo Liu
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | | | | | | | | | | - Toni Widmer
- Chemical
and Pharmaceutical Profiling, Global Drug Development, Novartis Pharma AG, CH-4002 Basel, Switzerland
| | - Ben Wen
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | | |
Collapse
|
|
35
|
Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases. J Membr Biol 2017; 251:369-378. [PMID: 29260282 DOI: 10.1007/s00232-017-0008-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 12/12/2017] [Indexed: 10/18/2022]
Abstract
Proteases, sharp yet unforgivable tools of every cell, require tight regulation to ensure specific non-aberrant cleavages. The relatively recent discovered class of intramembrane proteases has gained increasing interest due to their involvement in important signaling pathways linking them to diseases including Alzheimer's disease and cancer. Despite tremendous efforts, their regulatory mechanisms have only started to unravel. There is evidence that the membrane composition itself can regulate intramembrane protease activity and specificity. In this review, we highlight the work on γ-secretase and rhomboid proteases and summarize several studies as to how different lipids impact on enzymatic activity.
Collapse
|
|
36
|
Mentrup T, Fluhrer R, Schröder B. Latest emerging functions of SPP/SPPL intramembrane proteases. Eur J Cell Biol 2017; 96:372-382. [DOI: 10.1016/j.ejcb.2017.03.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/28/2017] [Accepted: 03/02/2017] [Indexed: 10/20/2022] Open
|
|
37
|
Zhang X, Götte M, Ibig-Rehm Y, Schuffenhauer A, Kamke M, Beisner D, Guerini D, Siebert D, Bonamy GMC, Gabriel D, Bodendorf U. Identification of SPPL2a Inhibitors by Multiparametric Analysis of a High-Content Ultra-High-Throughput Screen. SLAS DISCOVERY 2017; 22:1106-1119. [PMID: 28731783 DOI: 10.1177/2472555217719834] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The intramembrane protease signal peptide peptidase-like 2a (SPPL2a) is a potential drug target for the treatment of autoimmune diseases due to an essential role in B cells and dendritic cells. To screen a library of 1.4 million compounds for inhibitors of SPPL2a, we developed an imaging assay detecting nuclear translocation of the proteolytically released cytosolic substrate fragment. The state-of-the-art hit calling approach based on nuclear translocation resulted in numerous false-positive hits, mainly interrupting intracellular protein trafficking. To filter the false positives, we extracted 340 image-based readouts and developed a novel multiparametric analysis method that successfully triaged the primary hit list. The identified scaffolds were validated by demonstrating activity on endogenous SPPL2a and substrate CD74/p8 in B cells. The multiparametric analysis discovered diverse cellular phenotypes and provided profiles for the whole library. The principle of the presented imaging assay, the screening strategy, and multiparametric analysis are potentially applicable in future screening campaigns.
Collapse
Affiliation(s)
- Xian Zhang
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Marjo Götte
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | | | - Marion Kamke
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Dan Beisner
- Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA.,Vividion Therapeutics, San Diego, CA, USA
| | - Danilo Guerini
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Daniela Siebert
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | - Daniela Gabriel
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | |
Collapse
|
|
38
|
Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017. [PMID: 28624439 DOI: 10.1016/j.bbamcr.2017.06.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Signal peptide peptidase (SPP) and the four homologous SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 are GxGD-type intramembrane-cleaving proteases (I-CLIPs). In addition to divergent subcellular localisations, distinct differences in the mechanistic properties and substrate requirements of individual family members have been unravelled. SPP/SPPL proteases employ a catalytic mechanism related to that of the γ-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and γ-secretase by inhibitors has been demonstrated. Furthermore, also within the SPP/SPPL family significant differences in the sensitivity to currently available inhibitory compounds have been reported. Though far from complete, our knowledge on pathophysiological functions of SPP/SPPL proteases, in particular based on studies in mice, has been significantly increased over the last years. Based on this, inhibition of distinct SPP/SPPL proteases has been proposed as a novel therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections, as we will discuss in this review. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
Collapse
|
|
39
|
Schneppenheim J, Loock AC, Hüttl S, Schweizer M, Lüllmann-Rauch R, Oberg HH, Arnold P, Lehmann CHK, Dudziak D, Kabelitz D, Lucius R, Lennon-Duménil AM, Saftig P, Schröder B. The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments. THE JOURNAL OF IMMUNOLOGY 2017; 199:172-185. [DOI: 10.4049/jimmunol.1601533] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 05/01/2017] [Indexed: 01/24/2023]
|
|
40
|
Invariant Chain Complexes and Clusters as Platforms for MIF Signaling. Cells 2017; 6:cells6010006. [PMID: 28208600 PMCID: PMC5371871 DOI: 10.3390/cells6010006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 02/05/2017] [Accepted: 02/07/2017] [Indexed: 12/24/2022] Open
Abstract
Invariant chain (Ii/CD74) has been identified as a surface receptor for migration inhibitory factor (MIF). Most cells that express Ii also synthesize major histocompatibility complex class II (MHC II) molecules, which depend on Ii as a chaperone and a targeting factor. The assembly of nonameric complexes consisting of one Ii trimer and three MHC II molecules (each of which is a heterodimer) has been regarded as a prerequisite for efficient delivery to the cell surface. Due to rapid endocytosis, however, only low levels of Ii-MHC II complexes are displayed on the cell surface of professional antigen presenting cells and very little free Ii trimers. The association of Ii and MHC II has been reported to block the interaction with MIF, thus questioning the role of surface Ii as a receptor for MIF on MHC II-expressing cells. Recent work offers a potential solution to this conundrum: Many Ii-complexes at the cell surface appear to be under-saturated with MHC II, leaving unoccupied Ii subunits as potential binding sites for MIF. Some of this work also sheds light on novel aspects of signal transduction by Ii-bound MIF in B-lymphocytes: membrane raft association of Ii-MHC II complexes enables MIF to target Ii-MHC II to antigen-clustered B-cell-receptors (BCR) and to foster BCR-driven signaling and intracellular trafficking.
Collapse
|
|
41
|
Chang H, Smallwood PM, Williams J, Nathans J. Intramembrane Proteolysis of Astrotactins. J Biol Chem 2017; 292:3506-3516. [PMID: 28100779 DOI: 10.1074/jbc.m116.768077] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 01/14/2017] [Indexed: 11/06/2022] Open
Abstract
Astrotactins are vertebrate-specific membrane proteins implicated in neuron-glia interactions during central nervous system development and in hair follicle polarity during skin development. By studying epitope-tagged derivatives of mouse astrotactin-2 (Astn2) produced in transfected cells, we determined that the amino and carboxyl termini reside in the extracellular space and are initially linked by two transmembrane segments and a single cytoplasmic domain. We further show that Astn2 undergoes proteolytic cleavage in the second transmembrane domain (TM2) and that a disulfide bond holds the resulting two fragments together. Recombinant Astn1 also undergoes TM2 cleavage, as does Astn2 isolated from mouse cerebellum. Astn2 intramembrane proteolysis is insensitive to replacement of TM2 by the transmembrane domain of CD74 or by 21 alanines. However, replacement of TM2 by the transmembrane domain of CD4, the asialoglycoprotein receptor, or the transferrin receptor eliminates intramembrane proteolysis, as does leucine substitution of residues that overlap or are immediately upstream of the cleavage site. Replacement of the transmembrane domain of CD74 or the asialoglycoprotein receptor with Astn2 TM2 leads to the appearance of a carboxyl-terminal fragment consistent with intramembrane proteolysis. These experiments define a highly unusual transmembrane topology for the astrotactins, reveal intramembrane proteolysis as a feature of astrotactin maturation, and constrain the substrate sequences that are permissive for cleavage of one type 2 transmembrane segment.
Collapse
Affiliation(s)
- Hao Chang
- Departments of Molecular Biology and Genetics
| | | | | | - Jeremy Nathans
- Departments of Molecular Biology and Genetics; Neuroscience; Ophthalmology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
| |
Collapse
|
|
42
|
Verhelst SHL. Intramembrane proteases as drug targets. FEBS J 2017; 284:1489-1502. [PMID: 27889944 DOI: 10.1111/febs.13979] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 11/14/2016] [Accepted: 11/24/2016] [Indexed: 01/04/2023]
Abstract
Proteases are considered attractive drug targets. Various drugs targeting classical, soluble proteases have been approved for treatment of human disease. Intramembrane proteases (IMPs) are a more recently discovered group of proteolytic enzymes. They are embedded in lipid bilayers and their active sites are located in the plane of a membrane. All four mechanistic families of IMPs have been linked to disease, but currently, no drugs against IMPs have entered the market. In this review, I will outline the function of IMPs with a focus on the ones involved in human disease, which includes Alzheimer's disease, cancer, and infectious diseases by microorganisms. Inhibitors of IMPs are known for all mechanistic classes, but are not yet very potent or selective - aside from those targeting γ-secretase. I will here describe the different features of IMP inhibitors and discuss a list of issues that need attention in the near future in order to improve the drug development for IMPs.
Collapse
Affiliation(s)
- Steven H L Verhelst
- Department of Cellular and Molecular Medicine, KU Leuven - University of Leuven, Belgium.,AG Chemical Proteomics, Leibniz Institute for Analytical Sciences ISAS, Dortmund, Germany
| |
Collapse
|
|
43
|
Schröder B, Saftig P. Intramembrane proteolysis within lysosomes. Ageing Res Rev 2016; 32:51-64. [PMID: 27143694 DOI: 10.1016/j.arr.2016.04.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/01/2016] [Accepted: 04/26/2016] [Indexed: 11/26/2022]
Abstract
Regulated intramembrane proteolysis is of pivotal importance in a diverse set of developmental and physiological processes. Altered intramembrane substrate turnover may be associated with neurodegeneration, cancer and impaired immune function. In this review we will focus on the intramembrane proteases which have been localized in the lysosomal membrane. Members of the γ-secretase complex and γ-secretase activity are found in the lysosomal membrane and are discussed to contribute to intracellular amyloid β production. Mutant or deficient γ-secretase may cause disturbed lysosomal function. The signal peptide peptidase-like (SPPL) protease 2a is a lysosomal membrane component and cleaves CD74, the invariant chain of the MHC II complex, as well as FasL, TNF, ITM2B and TMEM106, type II transmembrane proteins involved in the regulation of immunity and neurodegeneration. Therefore, it can be concluded, that not only proteolysis within the lysosomal lumen but also within lysosomal membranes regulates important cellular functions and contributes essentially to proteostasis of membrane proteins what may become increasingly compromised in the aged individual.
Collapse
|
|
44
|
The biological function and significance of CD74 in immune diseases. Inflamm Res 2016; 66:209-216. [DOI: 10.1007/s00011-016-0995-1] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 09/30/2016] [Indexed: 12/25/2022] Open
|
|
45
|
Relationship between elevated soluble CD74 and severity of experimental and clinical ALI/ARDS. Sci Rep 2016; 6:30067. [PMID: 27444250 PMCID: PMC4957083 DOI: 10.1038/srep30067] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 06/28/2016] [Indexed: 01/11/2023] Open
Abstract
CD74 is expressed on the cell surface of pulmonary macrophages and contributes to macrophage migration inhibitory factor (MIF)-induced inflammatory response in acute lung injury (ALI). A circulating form of CD74 (soluble CD74, sCD74) was recently discovered in autoimmune liver disease. Using two murine ALI models and cells culture, we examined the presence of sCD74 in circulation and alveolar space and preliminarily assessed the biological function of sCD74. The concentrations of sCD74 were increased in serum and bronchoalveolar lavage fluids (BALF) of murine ALI models. The elevated levels of sCD74 in BALF positively correlated with lung permeability and inflammation. In addition, sCD74 is secreted by macrophages in response to MIF stimulation and itself can stimulate the production of inflammatory cytokines. Our clinical study confirmed some findings of basic research. Moreover, we also found Day 3 serum sCD74 levels were associated with worse clinical outcomes. In conclusion, higher serum sCD74 levels may reflect more severe lung injury and may be used to help physicians determine prognosis of acute respiratory distress syndrome (ARDS).
Collapse
|
|
46
|
Oh J, Shin JS. Molecular mechanism and cellular function of MHCII ubiquitination. Immunol Rev 2016; 266:134-44. [PMID: 26085212 DOI: 10.1111/imr.12303] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The major histocompatibility complex class II (MHCII) is ubiquitinated via the evolutionarily conserved lysine in the cytoplasmic tail of the β chain in dendritic cells (DCs) and B cells. The ubiquitination is mediated by the membrane-associated RING-CH1 (MARCH1) ubiquitin ligase although it can be also mediated by the homologous ligase MARCH8 in model cell lines. The ubiquitination promotes MHCII endocytosis and lysosomal sorting that results in a reduction in the level of MHCII at cell surface. Functionally, MHCII ubiquitination serves as a means by which DCs suppress MHCII expression and reduce antigen presentation in response to the immune regulatory cytokine interleukin-10 (IL-10) and regulatory T cells. Recently, additional roles of MHCII ubiquitination have emerged. MHCII ubiquitination promoted DC production of inflammatory cytokines in response to the Toll-like receptor ligands. It also potentiated DC ability to activate antigen-specific naive CD4(+) T cells while limiting the amount of antigens presented at cell surface. Similarly, MHCII ubiquitination promoted DC activation of CD4(+) thymocytes supporting regulatory T-cell development independent of its effect of limiting antigen presentation. Thus, ubiquitination appears to confer MHCII a function independent of presenting antigens by a mechanism yet to be identified.
Collapse
Affiliation(s)
- Jaehak Oh
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA, USA
| | - Jeoung-Sook Shin
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
47
|
Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. Biochem J 2016; 473:1405-22. [DOI: 10.1042/bcj20160156] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/16/2016] [Indexed: 11/17/2022]
Abstract
Intramembrane proteolysis of CD74 by SPPL2a is essential for B- and dendritic cells. We show that CD74 is proteolysed in the luminal third of the transmembrane segment and identify determinants within its transmembrane and luminal membrane-proximal domain facilitating this cleavage.
Collapse
|
|
48
|
Schröder B. The multifaceted roles of the invariant chain CD74--More than just a chaperone. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1269-81. [PMID: 27033518 DOI: 10.1016/j.bbamcr.2016.03.026] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 03/22/2016] [Accepted: 03/23/2016] [Indexed: 01/13/2023]
Abstract
The invariant chain (CD74) is well known for its essential role in antigen presentation by mediating assembly and subcellular trafficking of the MHCII complex. Beyond this, CD74 has also been implicated in a number of processes independent of MHCII. These include the regulation of endosomal trafficking, cell migration and cellular signalling as surface receptor of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). In several forms of cancer, CD74 is up-regulated and associated with enhanced proliferation and metastatic potential. In this review, an overview of the diverse biological functions of the CD74 protein is provided with a particular focus on how these may be regulated. In particular, proteolysis of CD74 will be discussed as a central mechanism to control the actions of this important protein at different levels.
Collapse
Affiliation(s)
- Bernd Schröder
- Biochemical Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Germany.
| |
Collapse
|
|
49
|
Unanue ER, Turk V, Neefjes J. Variations in MHC Class II Antigen Processing and Presentation in Health and Disease. Annu Rev Immunol 2016; 34:265-97. [PMID: 26907214 DOI: 10.1146/annurev-immunol-041015-055420] [Citation(s) in RCA: 184] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
MHC class II (MHC-II) molecules are critical in the control of many immune responses. They are also involved in most autoimmune diseases and other pathologies. Here, we describe the biology of MHC-II and MHC-II variations that affect immune responses. We discuss the classic cell biology of MHC-II and various perturbations. Proteolysis is a major process in the biology of MHC-II, and we describe the various components forming and controlling this endosomal proteolytic machinery. This process ultimately determines the MHC-II-presented peptidome, including cryptic peptides, modified peptides, and other peptides that are relevant in autoimmune responses. MHC-II also variable in expression, glycosylation, and turnover. We illustrate that MHC-II is variable not only in amino acids (polymorphic) but also in its biology, with consequences for both health and disease.
Collapse
Affiliation(s)
- Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110;
| | - Vito Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, SI-1000 Ljubljana, Slovenia;
| | - Jacques Neefjes
- Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; .,Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| |
Collapse
|
|
50
|
Hamblet CE, Makowski SL, Tritapoe JM, Pomerantz JL. NK Cell Maturation and Cytotoxicity Are Controlled by the Intramembrane Aspartyl Protease SPPL3. THE JOURNAL OF IMMUNOLOGY 2016; 196:2614-26. [PMID: 26851218 DOI: 10.4049/jimmunol.1501970] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 01/16/2016] [Indexed: 11/19/2022]
Abstract
NK cell maturation is critical for normal effector function and the innate immune response to tumors and pathogens. However, the molecular pathways that control NK cell maturation remain largely undefined. In this article, we investigate the role of SPPL3, an intramembrane aspartyl protease, in murine NK cell biology. We find that deletion of SPPL3 in the hematopoietic system reduces numbers of peripheral NK cells, clearance of MHC class I-deficient tumors in vivo, and cytotoxicity against tumor cells in vitro. This phenotype is concomitant with reduced numbers of CD27(+)CD11b(+) and CD27(-)CD11b(+) NK cells, indicating a requirement for SPPL3 in efficient NK cell maturation. NK cell-specific deletion of SPPL3 results in the same deficiencies, revealing a cell-autonomous role for SPPL3 in these processes. CRISPR/Cas9 genomic editing in murine zygotes was used to generate knockin mice with a catalytically compromised SPPL3 D271A allele. Mice engineered to express only SPPL3 D271A in NK cells phenocopy mice deleted for SPPL3, indicating a requirement for SPPL3 protease activity in NK cell biology. Our results identify SPPL3 as a cell-autonomous molecular determinant of NK cell maturation and expand the role of intramembrane aspartyl proteases in innate immunity.
Collapse
Affiliation(s)
- Corinne E Hamblet
- Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Stefanie L Makowski
- Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Julia M Tritapoe
- Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Joel L Pomerantz
- Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
| |
Collapse
|