Halder UC, Bhowmick R, Roy Mukherjee T, Nayak MK, Chawla-Sarkar M

During infection, viral proteins target cellular pathways that regulate cellular innate immune responses and cell death. We demonstrate that influenza A virus matrix protein 1(M1), an established pro-apoptotic protein, activates the nuclear factor-κB member RelB mediated survival genes (cIAP1, cIAP2 and c-flip), a function which is linked with its nuclear ...

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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 protein binds to and stabilizes Daxx protein by preventing its ubiquitination and proteosomal degradation. Binding of M1 with Daxx through its Daxx binding motif (DBM) prevents binding of RelB and Daxx resulting in upregulation of survival genes. This interaction also prevents promoter recruitment of DNA methyl transferases (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 survival role. In addition to nuclear localization signal (NLS), translocation of M1 to nucleus depends on cellular kinase mediated phosphorylation, as 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.

Date: Apr. 02, 2013

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