title: Cell death regulation during influenza A virus infection by matrix (M1) protein: a model of viral control over the cellular survival pathway.
abstract: During early infection, viruses activate cellular stress-response proteins such as heat-shock proteins (Hsps) to counteract apoptosis, but later on, they modulate these proteins to stimulate apoptosis for efficient viral dissemination. Hsp70 has been attributed to modulate viral entry, transcription, nuclear translocation and virion formation. It also exerts its anti-apoptotic function by binding to apoptosis protease-activating factor 1 (Apaf-1) and disrupting apoptosome formation. Here, we show that influenza A virus can regulate the anti-apoptotic function of Hsp70 through viral protein M1 (matrix 1). M1 itself did not induce apoptosis, but enhanced the effects of apoptotic inducers. M1-small-interfering RNA inhibits virus-induced apoptosis in cells after either virus infection or overexpression of the M1 protein. M1 binds to Hsp70, which results in reduced interaction between Hsp70 and Apaf-1. In a cell-free system, the M1 protein mediates procaspase-9 activation induced by cytochrome c/deoxyadenosine triphosphate. A study involving deletion mutants confirmed the role of the C-terminus substrate-binding domain (EEVD) of Hsp70 and amino acids 128-165 of M1 for this association. The M1 mutants, which did not co-immunoprecipitate with Hsp70, failed to induce apoptosis. Overall, the study confirms the proapoptotic function of the M1 protein during influenza virus infection.
authors: Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India.
authors: U C
authors: UC
authors: Halder
authors: P
authors: P
authors: Bagchi
authors: S
authors: S
authors: Chattopadhyay
authors: D
authors: D
authors: Dutta
authors: M
authors: M
authors: Chawla-Sarkar
mesh_terms: D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D003838:Deoxyadenine Nucleotides; D018840:HSP70 Heat-Shock Proteins; C488936:M1 protein, Influenza A virus; D034741:RNA, Small Interfering; D014763:Viral Matrix Proteins; D045304:Cytochromes c; D053453:Caspase 9; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate