Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1.

TitleCoxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1.
Publication TypeJournal Article
Year of Publication2010
AuthorsZhang, HM, Ye, X, Su, Y, Yuan, J, Liu, Z, Stein, DA, Yang, D
JournalJ Virol
Volume84
Issue17
Pagination8446-59
Date Published2010 Sep
ISSN1098-5514
KeywordsAnimals, Apoptosis, Caspase 12, Coxsackievirus Infections, Down-Regulation, Endoplasmic Reticulum, Enterovirus, Eukaryotic Initiation Factor-2, HeLa Cells, HSP40 Heat-Shock Proteins, Humans, Mice, Myocytes, Cardiac, Phosphorylation, Sterol Regulatory Element Binding Protein 1, Transcription Factor CHOP, Unfolded Protein Response
Abstract

Cardiomyocyte apoptosis is a hallmark of coxsackievirus B3 (CVB3)-induced myocarditis. We used cardiomyocytes and HeLa cells to explore the cellular response to CVB3 infection, with a focus on pathways leading to apoptosis. CVB3 infection triggered endoplasmic reticulum (ER) stress and differentially regulated the three arms of the unfolded protein response (UPR) initiated by the proximal ER stress sensors ATF6a (activating transcription factor 6a), IRE1-XBP1 (X box binding protein 1), and PERK (PKR-like ER protein kinase). Upon CVB3 infection, glucose-regulated protein 78 expression was upregulated, and in turn ATF6a and XBP1 were activated via protein cleavage and mRNA splicing, respectively. UPR activity was further confirmed by the enhanced expression of UPR target genes ERdj4 and EDEM1. Surprisingly, another UPR-associated gene, p58(IPK), which often is upregulated during infections with other types of viruses, was downregulated at both mRNA and protein levels after CVB3 infection. These findings were observed similarly for uninfected Tet-On HeLa cells induced to overexpress ATF6a or XBP1. In exploring potential connections between the three UPR pathways, we found that the ATF6a-induced downregulation of p58(IPK) was associated with the activation of PKR (PERK) and the phosphorylation of eIF2alpha, suggesting that p58(IPK), a negative regulator of PERK and PKR, mediates cross-talk between the ATF6a/IRE1-XBP1 and PERK arms. Finally, we found that CVB3 infection eventually produced the induction of the proapoptoic transcription factor CHOP and the activation of SREBP1 and caspase-12. Taken together, these data suggest that CVB3 infection activates UPR pathways and induces ER stress-mediated apoptosis through the suppression of P58(IPK) and induction/activation of CHOP, SREBP1, and caspase-12.

DOI10.1128/JVI.01416-09
Alternate JournalJ. Virol.
PubMed ID20554776
PubMed Central IDPMC2918999
Grant List / / Canadian Institutes of Health Research / Canada