title: Enhanced enteroviral infectivity via viral protease-mediated cleavage of Grb2-associated binder 1.
abstract: Coxsackievirus B3 (CVB3), an important human causative pathogen for viral myocarditis, pancreatitis, and meningitis, has evolved different strategies to manipulate the host signaling machinery to ensure successful viral infection. We previously revealed a crucial role for the ERK1/2 signaling pathway in regulating viral infectivity. However, the detail mechanism remains largely unknown. Grb2-associated binder 1 (GAB1) is an important docking protein responsible for intracellular signaling assembly and transduction. In this study, we demonstrated that GAB1 was proteolytically cleaved after CVB3 infection at G175 and G436 by virus-encoded protease 2A(pro), independent of caspase activation. Knockdown of GAB1 resulted in a significant reduction of viral protein expression and virus titers. Moreover, we showed that virus-induced cleavage of GAB1 is beneficial to viral growth as the N-terminal proteolytic product of GAB1 (GAB1-N1-174) further enhances ERK1/2 activation and promotes viral replication. Our results collectively suggest that CVB3 targets host GAB1 to generate a GAB1-N1-174 fragment that enhances viral infectivity, at least in part, via activation of the ERK pathway. The findings in this study suggest a novel mechanism that CVB3 employs to subvert the host signaling and facilitate consequent viral replication.
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Deng
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fung
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Shi
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yin
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA honglin.luo@hli.ubc.ca zheng-gen_jin@urmc.rochester.edu.
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Jin
authors.affiliation: *Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA honglin.luo@hli.ubc.ca zheng-gen_jin@urmc.rochester.edu.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D003384:Coxsackievirus Infections / Q000235:genetics / Q000378:metabolism; D029822:Enterovirus B, Human / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D014764:Viral Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010447:Peptide Hydrolases; D020169:Caspases
keywords: ERK1/2; coxsackievirus B3; signal transduction; viral protease 2Apro