title: Phosphorylation drives an apoptotic protein to activate antiapoptotic genes: paradigm of influenza A matrix 1 protein function.
abstract: During infection, viral proteins target cellular pathways that regulate cellular innate immune responses and cell death. We demonstrate that influenza A virus matrix 1 protein (M1), an established proapoptotic protein, activates nuclear factor-κB member RelB-mediated survival genes (cIAP1, cIAP2, and cFLIP), a function that is linked with its nuclear translocation during early infection. Death domain-associated protein 6 (Daxx) is a transcription co-repressor of the RelB-responsive gene promoters. During influenza virus infection M1 binds to and stabilizes Daxx protein by preventing its ubiquitination and proteasomal degradation. Binding of M1 with Daxx through its Daxx binding motif prevents binding of RelB and Daxx, resulting in up-regulation of survival genes. This interaction also prevents promoter recruitment of DNA methyltransferases (Dnmt1 and Dnmt3a) and lowers CpG methylation of the survival gene promoters, leading to the activation of these genes. Thus, M1 prevents repressional function of Daxx during infection, thereby exerting a survival role. In addition to its nuclear localization signal, translocation of M1 to the nucleus depends on cellular kinase-mediated phosphorylation as the protein kinase C inhibitor calphostin C effectively down-regulates virus replication. The study reconciles the ambiguity of dual antagonistic function of viral protein and potentiates a possible target to limit virus infection.
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme-XM, Beliaghata, Kolkata 700010, India.
authors.forename: Umesh Chandra
authors.initials: UC
authors.lastname: Halder
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme-XM, Beliaghata, Kolkata 700010, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhowmick
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme-XM, Beliaghata, Kolkata 700010, India.
authors.forename: Tapasi
authors.initials: T
authors.lastname: Roy Mukherjee
authors.affiliation: Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.
authors.forename: Mukti Kant
authors.initials: MK
authors.lastname: Nayak
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, P-33 C.I.T. Road, Scheme-XM, Beliaghata, Kolkata 700010, India. Electronic address: sarkarmc@icmr.org.in.
authors.forename: Mamta
authors.initials: M
authors.lastname: Chawla-Sarkar
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D056970:Co-Repressor Proteins; D018899:CpG Islands; D004285:Dogs; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions; D051841:Transcription Factor RelB / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D051034:Inhibitor of Apoptosis Proteins; C488936:M1 protein, Influenza A virus; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C497593:RELB protein, human; D014763:Viral Matrix Proteins; D051841:Transcription Factor RelB
keywords: DNA Methylation; DNA Methyltransferase; Death Domain-associated Protein 6 (Daxx); Influenza Virus; Inhibitor of Apoptosis (IAP); Matrix 1 Protein; NF-κB Transcription Factor; Nuclear Translocation; Phosphorylation; RelB
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