Open AccessP58 IPK inhibits coxsackievirus‐induced apoptosis via the PI 3 K / A kt pathway requiring activation of ATF 6a and subsequent upregulation of mitofusin 2
Author(s) -
Zhang Huifang M.,
Qiu Ye,
Ye Xin,
Hemida Maged G.,
Hanson Paul,
Yang Decheng
Publication year - 2014
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12229
Subject(s) - downregulation and upregulation , protein kinase b , apoptosis , pi3k/akt/mtor pathway , biology , gene silencing , microbiology and biotechnology , small interfering rna , endoplasmic reticulum , transfection , programmed cell death , viability assay , phosphorylation , cell culture , signal transduction , biochemistry , gene , genetics
Summary Previously we found that prolonged endoplasmic reticulum ( ER ) stress caused by coxsackievirus B 3 ( CVB 3) infection led to p58 IPK downregulation and subsequent cell apoptosis. This finding implies that p58 IPK expression benefits cell survival and counteracts CVB 3‐induced apoptosis. In testing this hypothesis, we first found that PI 3 K / A kt survival pathway is more sensitive than ERK 1/2 in response to p58 IPK expression. This finding was further verified by silencing p58 IPK with specific siRNA s, which led to the significant suppression of phosphorylation of A kt (p‐ A kt) but not ERK 1/2. Further, using CVB 3‐infected cell line expressing dominant negative ATF 6a ( DN ‐ ATF 6a), we found that expression of p58 IPK and p‐ A kt was significantly reduced, which led to the decreased cell viability. However, when the DN ‐ ATF 6a cells were transiently transfected with p58 IPK , an opposite result was obtained. Finally, by CVB 3 infection of cells stably expressing p58 IPK , we found that CVB 3‐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 siRNA s or DN ‐ ATF 6a sensitized cells to CVB 3‐induced apoptosis. These results suggest that p58 IPK suppresses CVB 3‐induced apoptosis through selective activation of PI 3 K / A kt pathway that requires activation of ATF 6a and subsequently upregulates mitofusin 2.