title: P58(IPK) inhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2.
abstract: Previously we found that prolonged endoplasmic reticulum (ER) stress caused by coxsackievirus B3 (CVB3) infection led to p58(IPK) downregulation and subsequent cell apoptosis. This finding implies that p58(IPK) expression benefits cell survival and counteracts CVB3-induced apoptosis. In testing this hypothesis, we first found that PI3K/Akt survival pathway is more sensitive than ERK1/2 in response to p58(IPK) expression. This finding was further verified by silencing p58(IPK) with specific siRNAs, which led to the significant suppression of phosphorylation of Akt (p-Akt) but not ERK1/2. Further, using CVB3-infected cell line expressing dominant negative ATF6a (DN-ATF6a), we found that expression of p58(IPK) and p-Akt was significantly reduced, which led to the decreased cell viability. However, when the DN-ATF6a cells were transiently transfected with p58(IPK) , an opposite result was obtained. Finally, by CVB3 infection of cells stably expressing p58(IPK) , we found that CVB3-induced mitochondria-mediated apoptosis was suppressed, which was evidenced by the reduced cytochrome c release and upregulation of the mitochondrial membrane protein mitofusin 2. However, silencing p58(IPK) with either specific siRNAs or DN-ATF6a sensitized cells to CVB3-induced apoptosis. These results suggest that p58(IPK) suppresses CVB3-induced apoptosis through selective activation of PI3K/Akt pathway that requires activation of ATF6a and subsequently upregulates mitofusin 2.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Huifang M
authors.initials: HM
authors.lastname: Zhang
authors.forename: Ye
authors.initials: Y
authors.lastname: Qiu
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: Maged G
authors.initials: MG
authors.lastname: Hemida
authors.forename: Paul
authors.initials: P
authors.lastname: Hanson
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D003384:Coxsackievirus Infections; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004770:Enterovirus / Q000472:pathogenicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D020558:GTP Phosphohydrolases; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria; D024101:Mitochondrial Proteins; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015854:Up-Regulation
chemical_list: D051702:Activating Transcription Factor 6; D002070:Butadienes; D002867:Chromones; D045304:Cytochromes c; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; D050956:HSP40 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C497111:ATF6 protein, human; C494651:DNAJC3 protein, human; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C470018:MFN2 protein, human