Coxsackievirus B3 Infection Activates the Unfolded Protein Response and Induces Apoptosis through Downregulation of p58 ^IPK and Activation of CHOP and SREBP1

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 UPRassociated 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 eIF2␣, 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.

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…118,119 Other DNA and RNA oncolytic viruses have been reported to induce apoptotic cancer cell death (Tables 4 and 5). However, there are only two reports showing that virus-induced ecto-CRT was correlated with enhanced intratumoral infiltrations of immune subpopulations, which accounted for the 'in vivo' remarkable antitumor immunity.…”

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

“…For example, Hepatitis E virus (HEV) open reading frame 2 protein (ORF-2) is able to modulate ER stress induced apoptosis by increasing eIF2α phosphorylation and activation of CHOP, simultaneously (John, et al, 2011). Our lab also obtained a similar result in studying coxsackievirus B3 (CVB3)-induced apoptosis through phosphorylation of eIF2α and activation of CHOP; however, this activation is not through ATF4 but through ATF6 (Zhang, et al, 2010). For HEV, during infection, CHOP, which normally induces apoptosis and translocation of Bax to the mitochondria, is unable to perform this pro-apoptotic function.…”

MiR-21 confers resistance against CVB3-induced myocarditis by inhibiting PDCD4-mediated apoptosis

“…It is known that apoptosis and necrosis both contribute to the cell death in myocarditis [3]; however, a change in degree of necrosis was not seen with miR-21 levels over the course of infection indicating the protection role of miR-21 in CVB3-induced myocarditis might depend on regulation of apoptosis. It has been reported that CVB3 infection can dramatically induce myocardial apoptosis via death receptor-mediated and mitochondrial-mediated signaling pathways [28][29][30], and apoptosis is also o en evidenced in patients of acute myocarditis [31]. Additionally, anti-apoptosis approaches signi cantly improved CVB3-induced heart injury [32,33], further con rming the pathological role of apoptosis in the acute myocarditis.…”