title: Cleavage of Grb2-Associated Binding Protein 2 by Viral Proteinase 2A duringCoxsackievirusInfection.
abstract: Coxsackievirus type B3 (CV-B3), an enterovirus associated with the pathogenesis of several human diseases, subverts, or employs the host intracellular signaling pathways to support effective viral infection. We have previously demonstrated that Grb2-associated binding protein 1 (GAB1), a signaling adaptor protein that serves as a platform for intracellular signaling assembly and transduction, is cleaved upon CV-B3 infection, resulting in a gain-of-pro-viral-functionviathe modification of GAB1-mediated ERK1/2 pathway. GAB2 is a mammalian homolog of GAB1. In this study, we aim to address whether GAB2 plays a synergistic role with GAB1 in the regulation of CV-B3 replication. Here, we reported that GAB2 is also a target of CV-B3-encoded viral proteinase. We showed that GAB2 is cleaved at G238 during CV-B3 infection by viral proteinase 2A, generating two cleaved fragments of GAB2-N1-237and GAB2-C238-676. Moreover, knockdown of GAB2 significantly inhibits the synthesis of viral protein and subsequent viral progeny production, accompanied by reduced levels of phosphorylated p38, suggesting a pro-viral function for GAB2 linked to p38 activation. Finally, we examined whether the cleavage of GAB2 can promote viral replication as observed for GAB1 cleavage. We showed that expression of neither GAB2-N1-237nor GAB2-C238-676results in enhanced viral infectivity, indicating a loss-of-function, rather than a gain-of-function of GAB2 cleavage in mediating virus replication. Taken together, our findings in this study suggest a novel host defense machinery through which CV-B3 infection is limited by the cleavage of a pro-viral protein.
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British ColumbiaVancouver, BC, Canada; Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of MedicineShanghai, China.
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, BC, Canada.
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, BC, Canada.
authors.forename: Ye
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British ColumbiaVancouver, BC, Canada; Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical ScienceBeijing, China.
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, BC, Canada.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry Rochester, NY, USA.
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, BC, Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000502:physiology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D059748:Proteolysis; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus
keywords: CV-B3; GAB2; cleavage; viral proteinase 2A; virus