Article

Coxsackievirus B3 Infection Activates the Unfolded Protein Response and Induces Apoptosis through Downregulation of p58IPK and Activation of CHOP and SREBP1

Department of Pathology and Laboratory Medicine, University of British Columbia, The Providence Heart and Lung Institute, St Paul's Hospital, Vancouver, British Columbia, Canada.
Journal of Virology (Impact Factor: 4.44). 09/2010; 84(17):8446-59. DOI: 10.1128/JVI.01416-09
Source: PubMed

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.

  • Source
    • "Upon accumulation of unfolded proteins in the ER lumen, BiP is released from the UPR regulators (ATF6, IRE1 and PERK) leading to their activation (Hetz, 2012). It was demonstrated more than 10 years ago that viral infection can induce UPR (Waris et al., 2002) and later this has been confirmed for a range of viruses (Ambrose and Mackenzie, 2011; Barry et al., 2010; Huang et al., 2011; Pasqual et al., 2011; Zhang et al., 2010). The replication of viruses may either be inhibited or facilitated upon induction of UPR (Zhang and Wang, 2012). "
    Dataset: ER stress

    Full-text · Dataset · Sep 2015
  • Source
    • "Upon accumulation of unfolded proteins in the ER lumen, BiP is released from the UPR regulators (ATF6, IRE1 and PERK) leading to their activation (Hetz, 2012). It was demonstrated more than 10 years ago that viral infection can induce UPR (Waris et al., 2002) and later this has been confirmed for a range of viruses (Ambrose and Mackenzie, 2011; Barry et al., 2010; Huang et al., 2011; Pasqual et al., 2011; Zhang et al., 2010). The replication of viruses may either be inhibited or facilitated upon induction of UPR (Zhang and Wang, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Infectious salmon anemia virus (ISAV) is a salmon pathogen causing serious outbreaks in fish farms world-wide. There is currently no effective commercially available vaccine and there is a need for better understanding of host pathogen interactions with this virus. Various strains can cause both acute and persistent infections and therefore establish a balance with the host immune responses. We have studied host responses to this infection by analysing the main branches of the unfolded protein response (UPR) in salmon cells in vitro and in tissues from infected fish to gain a better understanding of virus - host interactions. ISAV induce the main symptoms and signalling pathways of UPR (ATF6, PERK and IRE1) without inducing translational attenuation. This may be due to concomitant induction of an important negative feedback loop via the phosphatase regulator GADD34. The host cells can therefore respond with translation of cytokine and antiviral proteins to curb or control infection. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Aug 2015 · Developmental and comparative immunology
  • Source
    • "For example, GCN2 has been shown to be activated and play antiviral functions in cells infected with human immunodeficiency virus 1 (HIV-1) (Cosnefroy et al., 2013) and in mice infected with mouse cytomegalovirus (Won et al., 2012), Semliki forest virus or Sindbis virus (Berlanga et al., 2006). Similarly, activation of PERK has been observed in cells infected with various DNA and RNA viruses, such as Coxsackievirus B3 (Zhang et al., 2010), vesicular stomatitis virus (VSV) (Baltzis et al., 2004), bovine viral diarrhea virus (Jordan et al., 2002) and herpes simplex virus 1 (HSV1) (Cheng et al., 2005), to name just a few. As for PKR, which is induced by interferon and activated by dsRNA of viral origin, extensive studies in a large number of DNA and RNA viruses have firmly established its antiviral activities (He, 2006; Langland et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Coronavirus replication is structurally and functionally associated with the endoplasmic reticulum (ER), a major site of protein synthesis, folding, modification and sorting in the eukaryotic cells. Disturbance of ER homeostasis may occur under various physiological or pathological conditions. In response to the ER stress, signaling pathways of the unfolded protein response (UPR) are activated. UPR is mediated by three ER transmembrane sensors, namely the PKR-like ER protein kinase (PERK), the inositol-requiring protein 1 (IRE1) and the activating transcriptional factor 6 (ATF6). UPR facilitates adaptation to ER stress by reversible translation attenuation, enhancement of ER protein folding capacity and activation of ER-associated degradation (ERAD). In cells under prolonged and irremediable ER stress, UPR can also trigger apoptotic cell death. Accumulating evidence has shown that coronavirus infection causes ER stress and induces UPR in the infected cells. UPR is closely associated with a number of major signaling pathways, including autophagy, apoptosis, the mitogen-activated protein (MAP) kinase pathways, innate immunity and pro-inflammatory response. Therefore, studies on the UPR are pivotal in elucidating the complicated issue of coronavirus-host interaction. In this paper, we present the up-to-date knowledge on coronavirus-induced UPR and discuss its potential involvement in regulation of innate immunity and apoptosis.
    Full-text · Article · Oct 2014 · Virus Research
Show more