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Xu J, Guo Y, Liu Q, Yang H, Ma M, Yu J, Chen L, Ou C, Liu X, Wu J. Pregabalin Mediates Retinal Ganglion Cell Survival From Retinal Ischemia/Reperfusion Injury Via the Akt/GSK3β/β-Catenin Signaling Pathway. Invest Ophthalmol Vis Sci 2022; 63:7. [PMID: 36326725 PMCID: PMC9645359 DOI: 10.1167/iovs.63.12.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Purpose Progressive retinal ganglion cell (RGC) loss induced by retinal ischemia/reperfusion (RIR) injury leads to irreversible visual impairment. Pregabalin (PGB) is a promising drug for neurodegenerative diseases. However, with regard to RGC survival, its specific role and exact mechanism after RIR injury remain unclear. In this study, we sought to investigate whether PGB could protect RGCs from mitochondria-related apoptosis induced by RIR and explore the possible mechanisms. Methods C57BL/6J mice and primary RGCs were pretreated with PGB prior to ischemia/reperfusion modeling. The retinal structure and cell morphology were assessed by immunochemical assays and optical coherence tomography. CCK8 was used to assay cell viability, and an electroretinogram was performed to detect RGC function. Mitochondrial damage was assessed by a reactive oxygen species (ROS) assay kit and transmission electron microscopy. Western blot and immunofluorescence assays quantified the expression of proteins associated with the Akt/GSK3β/β-catenin pathway. Results Treatment with PGB increased the viability of RGCs in vitro. Consistently, PGB preserved the normal thickness of the retina, upregulated Bcl-2, reduced the ratio of cleaved caspase-3/caspase-3 and the expression of Bax in vivo. Meanwhile, PGB improved mitochondrial structure and prevented excessive ROS production. Moreover, PGB restored the amplitudes of oscillatory potentials and photopic negative responses following RIR. The mechanisms underlying its neuroprotective effects were attributed to upregulation of the Akt/GSK3β/β-catenin pathway. However, PGB-mediated neuroprotection was suppressed when using MK2206 (an Akt inhibitor), whereas it was preserved when treated with TWS119 (a GSK3β inhibitor). Conclusions PGB exerts a protective effect against RGC apoptosis induced by RIR injury, mediated by the Akt/GSK3β/β-catenin pathway.
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Affiliation(s)
- Jing Xu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuyan Guo
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Liu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hui Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ming Ma
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Yu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Linjiang Chen
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunlian Ou
- Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaohui Liu
- Department of Ophthalmology, The Second People's Hospital of Foshan, Foshan, Guangdong, China
| | - Jing Wu
- Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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2
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Guerau-de-Arellano M, Piedra-Quintero ZL, Tsichlis PN. Akt isoforms in the immune system. Front Immunol 2022; 13:990874. [PMID: 36081513 PMCID: PMC9445622 DOI: 10.3389/fimmu.2022.990874] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 08/04/2022] [Indexed: 11/29/2022] Open
Abstract
Akt is a PI3K-activated serine-threonine kinase that exists in three distinct isoforms. Akt's expression in most immune cells, either at baseline or upon activation, reflects its importance in the immune system. While Akt is most highly expressed in innate immune cells, it plays crucial roles in both innate and adaptive immune cell development and/or effector functions. In this review, we explore what's known about the role of Akt in innate and adaptive immune cells. Wherever possible, we discuss the overlapping and distinct role of the three Akt isoforms, namely Akt1, Akt2, and Akt3, in immune cells.
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Affiliation(s)
- Mireia Guerau-de-Arellano
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States,Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United States,Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States,Department of Neuroscience, The Ohio State University, Columbus, OH, United States,The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States,*Correspondence: Mireia Guerau-de-Arellano,
| | - Zayda L. Piedra-Quintero
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Philip N. Tsichlis
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
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Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway. mBio 2021; 12:e0282421. [PMID: 34781737 PMCID: PMC8593687 DOI: 10.1128/mbio.02824-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/β-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/β-catenin pathway’s involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/β-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4+ T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8+ T cells. Mechanistically, induction of β-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides β-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the β-catenin pathway. Our data suggest that the Wnt/β-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus.
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Phosphor-IWS1-dependent U2AF2 splicing regulates trafficking of CAR-E-positive intronless gene mRNAs and sensitivity to viral infection. Commun Biol 2021; 4:1179. [PMID: 34635782 PMCID: PMC8505486 DOI: 10.1038/s42003-021-02668-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 08/24/2021] [Indexed: 12/28/2022] Open
Abstract
AKT-phosphorylated IWS1 promotes Histone H3K36 trimethylation and alternative RNA splicing of target genes, including the U2AF65 splicing factor-encoding U2AF2. The predominant U2AF2 transcript, upon IWS1 phosphorylation block, lacks the RS-domain-encoding exon 2, and encodes a protein which fails to bind Prp19. Here we show that although both U2AF65 isoforms bind intronless mRNAs containing cytoplasmic accumulation region elements (CAR-E), only the RS domain-containing U2AF65 recruits Prp19 and promotes their nuclear export. The loading of U2AF65 to CAR-Elements was RS domain-independent, but RNA PolII-dependent. Virus- or poly(I:C)-induced type I IFNs are encoded by genes targeted by the pathway. IWS1 phosphorylation-deficient cells therefore, express reduced levels of IFNα1/IFNβ1 proteins, and exhibit enhanced sensitivity to infection by multiple cytolytic viruses. Enhanced sensitivity of IWS1-deficient cells to Vesicular Stomatitis Virus and Reovirus resulted in enhanced apoptotic cell death via caspase activation. Inhibition of this pathway may therefore sensitize cancer cells to oncolytic viruses.
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5
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Wang C, Ruan L, Shi H, Lin W, Liu L, Li S. Phosphorylation of Shrimp Tcf by a Viral Protein Kinase WSV083 Suppresses Its Antiviral Effect. Front Immunol 2021; 12:698697. [PMID: 34408747 PMCID: PMC8365339 DOI: 10.3389/fimmu.2021.698697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022] Open
Abstract
Nuclear DNA-binding TCF proteins, which act as the main downstream effectors of Wnt signaling, are essential for the regulation of cell fate and innate immunity. However, their role during viral infection in shrimp remains unknown. Herein, we demonstrated that Litopenaeus vannamei TCF (LvTcf) acts independently of Lvβ-catenin to promote interferon-like protein LvVago1 production, thus mounting the response to WSSV infection. Further, we observed that WSV083, a WSSV serine/threonine protein kinase, bound to LvTcf and phosphorylated it. Phosphorylated LvTcf was then recognized and degraded via the ubiquitin-proteasome pathway. Moreover, mass spectrometry analyses indicated that the T39 and T104 residues of LvTcf were target sites phosphorylated by WSV083. Point mutation analyses suggested that additional sites of LvTcf may undergo phosphorylation via WSV083. Taken together, the current work provides valuable insights into host immunity and viral pathogenesis. LvTcf is not only a modulator of shrimp innate immunity but is also an important target for WSSV immune evasion. Thus, the current findings will help improve disease control in shrimps.
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Affiliation(s)
- Chuanqi Wang
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China.,School of Life Science, Xiamen University, Xiamen, China
| | - Lingwei Ruan
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China
| | - Hong Shi
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China
| | - Wenyang Lin
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China.,School of Life Science, Xiamen University, Xiamen, China
| | - Linmin Liu
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China
| | - Sujie Li
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of Ministry of Natural Resources, Third Institute of Oceanography, Ministry of Natural Resources, Fujian Key Laboratory of Marine Genetic Resources, Xiamen, China
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Chen J, Debebe A, Zeng N, Kopp J, He L, Sander M, Stiles BL. Transformation of SOX9 + cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma. Sci Rep 2021; 11:11823. [PMID: 34083580 PMCID: PMC8175600 DOI: 10.1038/s41598-021-90958-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/19/2021] [Indexed: 01/07/2023] Open
Abstract
SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.
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Affiliation(s)
- Jingyu Chen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Anketse Debebe
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Ni Zeng
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Janel Kopp
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Lina He
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Maike Sander
- Department of Pediatrics and Cellar and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
| | - Bangyan L Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
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7
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PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis. Int J Oral Sci 2021; 13:16. [PMID: 34011974 PMCID: PMC8134554 DOI: 10.1038/s41368-021-00123-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/17/2021] [Accepted: 03/28/2021] [Indexed: 01/11/2023] Open
Abstract
Circadian rhythm is involved in the development and diseases of many tissues. However, as an essential environmental regulating factor, its effect on amelogenesis has not been fully elucidated. The present study aims to investigate the correlation between circadian rhythm and ameloblast differentiation and to explore the mechanism by which circadian genes regulate ameloblast differentiation. Circadian disruption models were constructed in mice for in vivo experiments. An ameloblast-lineage cell (ALC) line was used for in vitro studies. As essential molecules of the circadian system, Bmal1 and Per2 exhibited circadian expression in ALCs. Circadian disruption mice showed reduced amelogenin (AMELX) expression and enamel matrix secretion and downregulated expression of BMAL1, PER2, PPARγ, phosphorylated AKT1 and β-catenin, cytokeratin-14 and F-actin in ameloblasts. According to previous findings and our study, BMAL1 positively regulated PER2. Therefore, the present study focused on PER2-mediated ameloblast differentiation and enamel formation. Per2 knockdown decreased the expression of AMELX, PPARγ, phosphorylated AKT1 and β-catenin, promoted nuclear β-catenin accumulation, inhibited mineralization and altered the subcellular localization of E-cadherin in ALCs. Overexpression of PPARγ partially reversed the above results in Per2-knockdown ALCs. Furthermore, in in vivo experiments, the length of incisor eruption was significantly decreased in the circadian disturbance group compared to that in the control group, which was rescued by using a PPARγ agonist in circadian disturbance mice. In conclusion, through regulation of the PPARγ/AKT1/β-catenin signalling axis, PER2 played roles in amelogenin expression, cell junctions and arrangement, enamel matrix secretion and mineralization during ameloblast differentiation, which exert effects on enamel formation.
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Agelidis A, Turturice BA, Suryawanshi RK, Yadavalli T, Jaishankar D, Ames J, Hopkins J, Koujah L, Patil CD, Hadigal SR, Kyzar EJ, Campeau A, Wozniak JM, Gonzalez DJ, Vlodavsky I, Li JP, Perkins DL, Finn PW, Shukla D. Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival. JCI Insight 2021; 6:144255. [PMID: 33621216 PMCID: PMC8119219 DOI: 10.1172/jci.insight.144255] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 02/18/2021] [Indexed: 01/03/2023] Open
Abstract
The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.
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Affiliation(s)
- Alex Agelidis
- Department of Microbiology and Immunology
- Department of Ophthalmology and Visual Sciences, and
| | - Benjamin A. Turturice
- Department of Microbiology and Immunology
- Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | | | - Dinesh Jaishankar
- Department of Ophthalmology and Visual Sciences, and
- Department of Dermatology, Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
| | - Joshua Ames
- Department of Microbiology and Immunology
- Department of Ophthalmology and Visual Sciences, and
| | - James Hopkins
- Department of Microbiology and Immunology
- Department of Ophthalmology and Visual Sciences, and
| | - Lulia Koujah
- Department of Microbiology and Immunology
- Department of Ophthalmology and Visual Sciences, and
| | | | | | - Evan J. Kyzar
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Anaamika Campeau
- Department of Pharmacology and
- Skaggs School of Pharmacy, UCSD, San Diego, La Jolla, California, USA
| | - Jacob M. Wozniak
- Department of Pharmacology and
- Skaggs School of Pharmacy, UCSD, San Diego, La Jolla, California, USA
| | - David J. Gonzalez
- Department of Pharmacology and
- Skaggs School of Pharmacy, UCSD, San Diego, La Jolla, California, USA
| | - Israel Vlodavsky
- Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Jin-ping Li
- Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden
| | - David L. Perkins
- Division of Nephrology, Department of Medicine, and
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Patricia W. Finn
- Department of Microbiology and Immunology
- Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Deepak Shukla
- Department of Microbiology and Immunology
- Department of Ophthalmology and Visual Sciences, and
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Marineau A, Khan KA, Servant MJ. Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids. Cells 2020; 9:cells9040897. [PMID: 32272583 PMCID: PMC7226782 DOI: 10.3390/cells9040897] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/03/2020] [Accepted: 04/05/2020] [Indexed: 12/23/2022] Open
Abstract
The rapid activation of the type I interferon (IFN) antiviral innate immune response relies on ubiquitously expressed RNA and DNA sensors. Once engaged, these nucleotide-sensing receptors use distinct signaling modules for the rapid and robust activation of mitogen-activated protein kinases (MAPKs), the IκB kinase (IKK) complex, and the IKK-related kinases IKKε and TANK-binding kinase 1 (TBK1), leading to the subsequent activation of the activator protein 1 (AP1), nuclear factor-kappa B (NF-κB), and IFN regulatory factor 3 (IRF3) transcription factors, respectively. They, in turn, induce immunomodulatory genes, allowing for a rapid antiviral cellular response. Unlike the MAPKs, the IKK complex and the IKK-related kinases, ubiquitously expressed glycogen synthase kinase 3 (GSK-3) α and β isoforms are active in unstimulated resting cells and are involved in the constitutive turnover of β-catenin, a transcriptional coactivator involved in cell proliferation, differentiation, and lineage commitment. Interestingly, studies have demonstrated the regulatory roles of both GSK-3 and β-catenin in type I IFN antiviral innate immune response, particularly affecting the activation of IRF3. In this review, we summarize current knowledge on the mechanisms by which GSK-3 and β-catenin control the antiviral innate immune response to RNA and DNA virus infections.
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Affiliation(s)
- Alexandre Marineau
- Faculty of Pharmacy, Université de Montréal, Montréal, QC H3C3J7, Canada;
| | - Kashif Aziz Khan
- Department of Biology, York University, Toronto, ON M3J1P3, Canada;
| | - Marc J. Servant
- Faculty of Pharmacy, Université de Montréal, Montréal, QC H3C3J7, Canada;
- Réseau Québécois de Recherche sur les Médicaments (RQRM), Montréal, QC H3T1C5, Canada
- Correspondence: ; Tel.: +1-514-343-7966
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You H, Lin Y, Lin F, Yang M, Li J, Zhang R, Huang Z, Shen Q, Tang R, Zheng C. β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein. J Virol 2020; 94:e01847-19. [PMID: 31801859 PMCID: PMC7022340 DOI: 10.1128/jvi.01847-19] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity.IMPORTANCE Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.
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Affiliation(s)
- Hongjuan You
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yingying Lin
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Feng Lin
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Mingyue Yang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Jiahui Li
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Rongzhao Zhang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zhiming Huang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Qingtang Shen
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chunfu Zheng
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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11
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Wang C, Ruan L, Shi H, Xu X. Wnt5b regulates apoptosis in Litopenaeus vannamei against white spot syndrome virus. FISH & SHELLFISH IMMUNOLOGY 2018; 74:318-324. [PMID: 29325710 DOI: 10.1016/j.fsi.2018.01.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 06/07/2023]
Abstract
The Wnt signaling mediated by Wnt proteins that orchestrate and influence a myriad of cellular processes, such as cell proliferation, differentiation, tumorigenesis, apoptosis, and participation in immune defense during microbe infection. Wnt5b is one of the Wnt signaling molecules that initiate the cascade. In this study, we cloned and characterized a Wnt5b homolog from Litopenaeus vannamei designed as LvWnt5b. The full length of LvWnt5b transcript was 1726 bp with an 1107 bp open reading frame that encoded a 368 aa protein, which contained 24 discontinuous and highly conserved cysteine. Real-time quantitative PCR showed that the transcriptional level of LvWnt5b was down-regulated when infected with white spot syndrome virus (WSSV). Knock-down of LvWnt5b resulted in inhibition of the transcriptional level of WSSV gene ie1, indicating that LvWnt5b mediated signaling pathway may play an important role in defense against WSSV infection. When LvWnt5b was silenced, caspase3/7 activity in hemocytes was increased significantly, and the transcription of viral gene was decreased as well. Moreover, overexpression of LvWnt5b in HEK293T cells led to inhibition of caspase3/7 activity, which further proved the role of LvWnt5b in restraining apoptosis. The study showed that the shrimp may decrease the expression of LvWnt5b initiatively to act as an immune defense mechanism against WSSV infection via promoting apoptosis. It will be helpful for understanding the function of Wnt signaling pathway in virus invasion and host defense.
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Affiliation(s)
- Chuanqi Wang
- School of Life Science, Xiamen University, Xiamen, 361005, PR China; State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of State Oceanic Administration, Third Institute of Oceanography, State Oceanic Administration, Fujian Key Laboratory of Marine Genetic Resources, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Xiamen, 361005, PR China
| | - Lingwei Ruan
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of State Oceanic Administration, Third Institute of Oceanography, State Oceanic Administration, Fujian Key Laboratory of Marine Genetic Resources, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Xiamen, 361005, PR China.
| | - Hong Shi
- State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of State Oceanic Administration, Third Institute of Oceanography, State Oceanic Administration, Fujian Key Laboratory of Marine Genetic Resources, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Xiamen, 361005, PR China
| | - Xun Xu
- School of Life Science, Xiamen University, Xiamen, 361005, PR China; State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources of State Oceanic Administration, Third Institute of Oceanography, State Oceanic Administration, Fujian Key Laboratory of Marine Genetic Resources, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Xiamen, 361005, PR China
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12
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Protein kinase B: emerging mechanisms of isoform-specific regulation of cellular signaling in cancer. Anticancer Drugs 2017; 28:569-580. [PMID: 28379898 DOI: 10.1097/cad.0000000000000496] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial-mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial-mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBβ (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance.
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13
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Wang X, Wang S, Li X, Jin S, Xiong F, Wang X. The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma. Onco Targets Ther 2017; 10:2781-2789. [PMID: 28615958 PMCID: PMC5460645 DOI: 10.2147/ott.s138908] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
To date, β-catenin has been reported to be implicated in mediating the epithelial-mesenchymal transition (EMT) in a variety of human cancers, which can be triggered by EGF. However, the mechanisms underlying EGF-β-catenin pathway-induced EMT of glioblastoma multiforme (GBM) have not been reported previously. In the present study, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blot were applied to investigate the effect of EGF-β-catenin pathway on EMT of GBM. Here, we identified that β-catenin mRNA and protein levels were up-regulated in GBM tissues and four kinds of glioblastoma cell lines, including T98G, A172, U87, and U251 cells, compared with normal brain tissue and astrocytes. In U87 cell line, inhibition of β-catenin by siRNA suppressed EGF-induced proliferation, migration, invasiveness, and the expression of EMT activators (Snail and Slug). In addition, the expression of epithelial markers (E-cadherin) was up-regulated and the expression of mesenchymal markers (N-cadherin and MMP9) was down-regulated. Finally, inhibitor of PI3K/Akt signaling pathways inactivated the EGF-β-catenin-induced EMT. In conclusion, β-catenin-EMT pathway induced by EGF is important for GBM progression by the PI3K/Akt pathways. Inhibition of β-catenin leads to suppression of EGF pathway-induced EMT, which provides a new way to treat GBM patients.
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Affiliation(s)
- Xingqiang Wang
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
| | - Shanshi Wang
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
| | - Xiaolong Li
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
| | - Shigang Jin
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
| | - Feng Xiong
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
| | - Xin Wang
- Department of Neurosurgery, People's Hospital of Rizhao, Jining Medical University, Rizhao, China
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Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening. Mol Cell 2017; 65:403-415.e8. [PMID: 28132841 DOI: 10.1016/j.molcel.2016.12.021] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 09/28/2016] [Accepted: 12/20/2016] [Indexed: 12/17/2022]
Abstract
Cell-autonomous induction of type I interferon must be stringently regulated. Rapid induction is key to control virus infection, whereas proper limitation of signaling is essential to prevent immunopathology and autoimmune disease. Using unbiased kinome-wide RNAi screening followed by thorough validation, we identified 22 factors that regulate RIG-I/IRF3 signaling activity. We describe a negative-feedback mechanism targeting RIG-I activity, which is mediated by death associated protein kinase 1 (DAPK1). RIG-I signaling triggers DAPK1 kinase activation, and active DAPK1 potently inhibits RIG-I stimulated IRF3 activity and interferon-beta production. DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation.
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15
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Zwezdaryk KJ, Combs JA, Morris CA, Sullivan DE. Regulation of Wnt/β-catenin signaling by herpesviruses. World J Virol 2016; 5:144-154. [PMID: 27878101 PMCID: PMC5105047 DOI: 10.5501/wjv.v5.i4.144] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 07/19/2016] [Accepted: 08/06/2016] [Indexed: 02/05/2023] Open
Abstract
The Wnt/β-catenin signaling pathway is instrumental in successful differentiation and proliferation of mammalian cells. It is therefore not surprising that the herpesvirus family has developed mechanisms to interact with and manipulate this pathway. Successful coexistence with the host requires that herpesviruses establish a lifelong infection that includes periods of latency and reactivation or persistence. Many herpesviruses establish latency in progenitor cells and viral reactivation is linked to host-cell proliferation and differentiation status. Importantly, Wnt/β-catenin is tightly connected to stem/progenitor cell maintenance and differentiation. Numerous studies have linked Wnt/β-catenin signaling to a variety of cancers, emphasizing the importance of Wnt/β-catenin pathways in development, tissue homeostasis and disease. This review details how the alpha-, beta-, and gammaherpesviruses interact and manipulate the Wnt/β-catenin pathway to promote a virus-centric agenda.
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16
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Suryawanshi A, Tadagavadi RK, Swafford D, Manicassamy S. Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer. Front Immunol 2016; 7:460. [PMID: 27833613 PMCID: PMC5081350 DOI: 10.3389/fimmu.2016.00460] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/12/2016] [Indexed: 12/02/2022] Open
Abstract
The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic autoimmune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade antitumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β-catenin pathway can be targeted for successful therapeutic interventions in various human diseases.
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Affiliation(s)
- Amol Suryawanshi
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | | | - Daniel Swafford
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Santhakumar Manicassamy
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA
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17
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β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites. Mol Cell Biol 2015; 36:13-29. [PMID: 26459757 DOI: 10.1128/mcb.00641-15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 10/02/2015] [Indexed: 12/12/2022] Open
Abstract
Rapid upregulation of interferon beta (IFN-β) expression following virus infection is essential to set up an efficient innate antiviral response. Biological roles related to the antiviral and immune response have also been associated with the constitutive production of IFN-β in naive cells. However, the mechanisms capable of modulating constitutive IFN-β expression in the absence of infection remain largely unknown. In this work, we demonstrate that inhibition of the kinase glycogen synthase kinase 3 (GSK-3) leads to the upregulation of the constitutive level of IFN-β expression in noninfected cells, provided that GSK-3 inhibition is correlated with the binding of β-catenin to the IFN-β promoter. Under these conditions, IFN-β expression occurred through the T-cell factor (TCF) binding sites present on the IFN-β promoter independently of interferon regulatory factor 3 (IRF3). Enhancement of the constitutive level of IFN-β per se was able to confer an efficient antiviral state to naive cells and acted in synergy with virus infection to stimulate virus-induced IFN-β expression. Further emphasizing the role of β-catenin in the innate antiviral response, we show here that highly pathogenic Rift Valley fever virus (RVFV) targets the Wnt/β-catenin pathway and the formation of active TCF/β-catenin complexes at the transcriptional and protein level in RVFV-infected cells and mice.
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18
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Campagnolo P, Hong X, di Bernardini E, Smyrnias I, Hu Y, Xu Q. Resveratrol-Induced Vascular Progenitor Differentiation towards Endothelial Lineage via MiR-21/Akt/β-Catenin Is Protective in Vessel Graft Models. PLoS One 2015; 10:e0125122. [PMID: 25961718 PMCID: PMC4427364 DOI: 10.1371/journal.pone.0125122] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/20/2015] [Indexed: 12/20/2022] Open
Abstract
Background and Purpose Vessel graft failure is typically associated with arteriosclerosis, in which endothelial dysfunction/damage is a key event. Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis. We aimed to study the influence of resveratrol on the behavior of resident stem cells that may contribute to graft arteriosclerosis. Experimental Approach Vascular resident progenitor cells and embryonic stem cells were treated with resveratrol under differentiating conditions and endothelial markers expression was evaluated. Expression of miR-21 and β-catenin was also tested and exogenously modified. Effects of resveratrol treatment in an ex vivo re-endothelialization model and on mice undergone vascular graft were evaluated. Key Results Resveratrol induced expression of endothelial markers such as CD31, VE-cadherin and eNOS in both progenitor and stem cells. We demonstrated that resveratrol significantly reduced miR-21 expression, which in turn reduced Akt phosphorylation. This signal cascade diminished the amount of nuclear β-catenin, inducing endothelial marker expression and increasing tube-like formation by progenitor cells. Both the inhibition of miR-21 and the knockdown of β-catenin were able to recapitulate the effect of resveratrol application. Ex vivo, progenitor cells treated with resveratrol produced better endothelialization of the decellularized vessel. Finally, in a mouse model of vessel graft, a resveratrol-enhanced diet was able to reduce lesion formation. Conclusions and Implications We provide the first evidence that oral administration of resveratrol can reduce neointimal formation in a model of vascular graft and elucidated the underpinning miR-21/Akt/β-catenin dependent mechanism. These findings may support the beneficial effect of resveratrol supplementation for graft failure prevention.
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Affiliation(s)
- Paola Campagnolo
- Cardiovascular Division, King’s College London BHF Centre, London, United Kingdom
- * E-mail: (PC); (QX)
| | - Xuechong Hong
- Cardiovascular Division, King’s College London BHF Centre, London, United Kingdom
| | | | - Ioannis Smyrnias
- Cardiovascular Division, King’s College London BHF Centre, London, United Kingdom
| | - Yanhua Hu
- Cardiovascular Division, King’s College London BHF Centre, London, United Kingdom
| | - Qingbo Xu
- Cardiovascular Division, King’s College London BHF Centre, London, United Kingdom
- * E-mail: (PC); (QX)
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19
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Yu H, Littlewood T, Bennett M. Akt isoforms in vascular disease. Vascul Pharmacol 2015; 71:57-64. [PMID: 25929188 PMCID: PMC4728195 DOI: 10.1016/j.vph.2015.03.003] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 03/31/2015] [Indexed: 11/05/2022]
Abstract
The mammalian serine/threonine Akt kinases comprise three closely related isoforms: Akt1, Akt2 and Akt3. Akt activation has been implicated in both normal and disease processes, including in development and metabolism, as well as cancer and cardiovascular disease. Although Akt signalling has been identified as a promising therapeutic target in cancer, its role in cardiovascular disease is less clear. Importantly, accumulating evidence suggests that the three Akt isoforms exhibit distinct tissue expression profiles, localise to different subcellular compartments, and have unique modes of activation. Consistent with in vitro findings, genetic studies in mice show distinct effects of individual Akt isoforms on the pathophysiology of cardiovascular disease. This review summarises recent studies of individual Akt isoforms in atherosclerosis, vascular remodelling and aneurysm formation, to provide a comprehensive overview of Akt function in vascular disease.
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Affiliation(s)
- Haixiang Yu
- Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
| | - Trevor Littlewood
- Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
| | - Martin Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
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20
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Swafford D, Manicassamy S. Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance. DISCOVERY MEDICINE 2015; 19:303-310. [PMID: 25977193 PMCID: PMC4513356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
A fundamental puzzle in immunology is how the immune system launches robust immunity against pathogens while maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront them every day. Innate immune cells, such as dendritic cells (DCs) and macrophages, play a fundamental role in this process. Emerging studies have highlighted that the Wnt signaling pathway, particularly in DCs, plays a major role in regulating tolerance versus immunity. Here, we review our current understanding of how Wnt-signaling shapes the immune response and, in addition, highlight unanswered questions, the solution of which will be imperative in the rational exploitation of this pathway in vaccine design and immune therapy.
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Affiliation(s)
- Daniel Swafford
- Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
| | - Santhakumar Manicassamy
- Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA
- Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA
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21
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Nurminskaya M, Beazley KE, Smith EP, Belkin AM. Transglutaminase 2 promotes PDGF-mediated activation of PDGFR/Akt1 and β-catenin signaling in vascular smooth muscle cells and supports neointima formation. J Vasc Res 2015; 51:418-28. [PMID: 25612735 DOI: 10.1159/000369461] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 10/25/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Phenotypic switch of vascular smooth muscle cells (VSMCs) accompanies neointima formation and associates with vascular diseases. Platelet-derived growth factor (PDGF)-induced activation of PDGFR/Akt1 and β-catenin signaling pathways in VSMCs has been implicated in vessel occlusion. Transglutaminase 2 (TG2) regulates these pathways and its levels are increased in the neointima. OBJECTIVE The aim of this study was to evaluate the role of TG2 in PDGF/β-catenin signaling cross-talk and assess its contribution to neointima. METHODS Aortic VSMCs from wild-type and TG2 knockout mice were tested in vitro for levels of VSMC markers, proliferation, migration and PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways. Neointima in these mice was studied ex vivo in coronary vessels using a heart slice model and in vivo using a carotid artery ligation model. RESULTS Genetic deletion of TG2 attenuated the PDGF-induced phenotypic switch of aortic VSMCs, reduced their proliferation and migration rates, and inhibited PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways in both ex vivo and in vivo neointima models. Importantly, genetic deletion of TG2 also markedly attenuated vessel occlusion. CONCLUSIONS TG2 promotes neointima formation by mediating the PDGF-induced activation of the PDGFR/Akt1 and β-catenin pathways in VSMCs. This study identifies TG2 as a potential therapeutic target for blocking neointima in blood vessels.
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Affiliation(s)
- Maria Nurminskaya
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Md., USA
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22
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Ma F, Liu SY, Razani B, Arora N, Li B, Kagechika H, Tontonoz P, Núñez V, Ricote M, Cheng G. Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon. Nat Commun 2014; 5:5494. [PMID: 25417649 PMCID: PMC4380327 DOI: 10.1038/ncomms6494] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/07/2014] [Indexed: 12/23/2022] Open
Abstract
The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.
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Affiliation(s)
- Feng Ma
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
| | - Su-Yang Liu
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
| | - Bahram Razani
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
| | - Neda Arora
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
| | - Bing Li
- Department of Biological Chemistry, University of California, Los Angeles, California 90095, USA
| | - Hiroyuki Kagechika
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Peter Tontonoz
- 1] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA [2] Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, USA
| | - Vanessa Núñez
- Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro 3, 28029 Madrid, Spain
| | - Mercedes Ricote
- Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro 3, 28029 Madrid, Spain
| | - Genhong Cheng
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA
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23
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Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 193:4203-13. [PMID: 25210120 DOI: 10.4049/jimmunol.1400614] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
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Affiliation(s)
- Indumathi Manoharan
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Yuan Hong
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Amol Suryawanshi
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | | | - Zuoming Sun
- Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010
| | - Andrew L Mellor
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
| | - David H Munn
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Santhakumar Manicassamy
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
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Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013; 19:1609-16. [PMID: 24216752 PMCID: PMC3855898 DOI: 10.1038/nm.3385] [Citation(s) in RCA: 169] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 09/20/2013] [Indexed: 12/17/2022]
Abstract
Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. PAR4 thrombin receptor induced platelet aggregation and calcium mobilization were significantly greater in black subjects. Numerous differentially expressed (DE) RNAs were associated with both race and PAR4 reactivity, including phosphatidylcholine transfer protein (PCTP), and platelets from blacks expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked activation of platelets or megakaryocytic cell lines through PAR4 but not PAR1. MiR-376c levels were DE by race and PAR4 reactivity, and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. MiR-376c regulated expression of PC-TP in human megakaryocytes. A disproportionately high number of miRNAs DE by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus, and were lower in platelets from blacks. These results support PC-TP as a regulator of the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race, and emphasize a need to consider race effects when developing anti-thrombotic drugs.
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Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M. Protein kinase A-dependent pSer(675) -β-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013; 58:1713-23. [PMID: 23744610 PMCID: PMC3800498 DOI: 10.1002/hep.26554] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 05/16/2013] [Accepted: 05/24/2013] [Indexed: 12/16/2022]
Abstract
UNLABELLED Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli disease (CD), and autosomal recessive polycystic kidney disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and β-catenin. In cholangiocytes isolated and cultured from Pkhd1(del4/del4) mice, stimulation of cAMP/PKA signaling (forskolin 10 μM) stimulated Ser(675) -phosphorylation of β-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 μM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1(del4/del4) cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer(675) -β-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1(del4/del4) and was inhibited by: (1) PKI, (2) silencing β-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. CONCLUSION These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer(675) -phosphorylation of β-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer(675) -β-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1(del4/del4) cholangiocytes. β-Catenin-dependent changes in cell motility may be central to the pathogenesis of the disease and represent a potential therapeutic target.
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Affiliation(s)
- Carlo Spirli
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Luigi Locatelli
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Carola M. Morell
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Romina Fiorotto
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Stuart D. Morton
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Massimiliano Cadamuro
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Luca Fabris
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Mario Strazzabosco
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA
- Department of InterdisciplinaryMedicine and Surgery, University of Milan-Bicocca, Milan, Italy
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Zhang Y, Wang X, Yang H, Liu H, Lu Y, Han L, Liu G. Kinase AKT controls innate immune cell development and function. Immunology 2013; 140:143-52. [PMID: 23692658 DOI: 10.1111/imm.12123] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 05/13/2013] [Accepted: 05/16/2013] [Indexed: 12/17/2022] Open
Abstract
The critical roles of kinase AKT in tumour cell proliferation, apoptosis and protein synthesis have been widely recognized. But AKT also plays an important role in immune modulation. Recent studies have confirmed that kinase AKT can regulate the development and functions of innate immune cells (neutrophil, macrophage and dendritic cell). Studies have shown that different isoforms of kinase AKT have different effects in regulating immunity-related diseases, mainly through the mammalian target of rapamycin-dependent or -independent pathways. The purpose of this review is to illustrate the immune modulating effects of kinase AKT on innate immune cell development, survival and function.
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Affiliation(s)
- Yan Zhang
- Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China; Shenyang Agriculture University, Shenyang, China
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Liu G, Bi Y, Wang R, Shen B, Zhang Y, Yang H, Wang X, Liu H, Lu Y, Han F. Kinase AKT1 negatively controls neutrophil recruitment and function in mice. THE JOURNAL OF IMMUNOLOGY 2013; 191:2680-90. [PMID: 23904165 DOI: 10.4049/jimmunol.1300736] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Neutrophils are critically involved in host defense and inflammatory injury. However, intrinsic signaling mechanisms controlling neutrophil recruitment and activities are poorly defined. In this article, we showed that protein kinase AKT1 (also known as PKBα) is the dominant isoform expressed in neutrophils and is downregulated upon bacterial infection and neutrophil activation. AKT1 deficiency resulted in severe disease progression accompanied by recruitment of neutrophils and enhanced bactericidal activity in the acute inflammatory lung injury (ALI) and the Staphylococcus aureus infection mouse models. Moreover, the depletion of neutrophils efficiently reversed the aggravated inflammatory response, but adoptive transfer of AKT1(-/-) neutrophils could potentiate the inflammatory immunity, indicating an intrinsic effect of the neutrophil in modulating inflammation in AKT1(-/-) mice. In the ALI model, the infiltration of neutrophils into the inflammatory site was associated with enhanced migration capacity, whereas inflammatory stimuli could promote neutrophil apoptosis. In accordance with these findings, neutralization of CXCR2 attenuated neutrophil infiltration and delayed the occurrence of inflammation. Finally, the enhanced bactericidal activity and inflammatory immunity of AKT-deficient neutrophils were mediated by a STAT1-dependent, but not a mammalian target of rapamycin-dependent, pathway. Thus, our findings indicated that the AKT1-STAT1 signaling axis negatively regulates neutrophil recruitment and activation in ALI and S. aureus infection in mice.
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Affiliation(s)
- Guangwei Liu
- Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200023, People's Republic of China.
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Baril M, Es-Saad S, Chatel-Chaix L, Fink K, Pham T, Raymond VA, Audette K, Guenier AS, Duchaine J, Servant M, Bilodeau M, Cohen É, Grandvaux N, Lamarre D. Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses. PLoS Pathog 2013; 9:e1003416. [PMID: 23785285 PMCID: PMC3681753 DOI: 10.1371/journal.ppat.1003416] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/26/2013] [Indexed: 12/24/2022] Open
Abstract
To identify new regulators of antiviral innate immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-β (IFNB1) promoter following Sendai virus (SeV) infection. We now report a novel link between WNT signaling pathway and the modulation of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-dependent innate immune responses. Here we show that secretion of WNT2B and WNT9B and stabilization of β-catenin (CTNNB1) upon virus infection negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF in a CTNNB1-dependent effector mechanism. The antiviral response is drastically reduced by glycogen synthase kinase 3 (GSK3) inhibitors but restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of antiviral innate immunity by a canonical-like WNT/CTNNB1 signaling pathway. The study identifies novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection.
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Affiliation(s)
- Martin Baril
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Salwa Es-Saad
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Laurent Chatel-Chaix
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Karin Fink
- Centre de Recherche du CHUM (CRCHUM), Hôpital Saint-Luc, Montréal, Québec, Canada
| | - Tram Pham
- Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Valérie-Ann Raymond
- Centre de Recherche du CHUM (CRCHUM), Hôpital Saint-Luc, Montréal, Québec, Canada
| | - Karine Audette
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Anne-Sophie Guenier
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Jean Duchaine
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
| | - Marc Servant
- Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada
| | - Marc Bilodeau
- Centre de Recherche du CHUM (CRCHUM), Hôpital Saint-Luc, Montréal, Québec, Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Éric Cohen
- Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Nathalie Grandvaux
- Centre de Recherche du CHUM (CRCHUM), Hôpital Saint-Luc, Montréal, Québec, Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Daniel Lamarre
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montréal, Québec, Canada
- Centre de Recherche du CHUM (CRCHUM), Hôpital Saint-Luc, Montréal, Québec, Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
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