The replication of coronavirus, a family of important animal and human pathogens, is closely associated with the cellular membrane compartments, especially the endoplasmic reticulum (ER). Coronavirus infection of cultured cells was previously shown to cause ER stress and induce the unfolded protein response (UPR), a process that aims to restore the ER homeostasis by global translation shutdown and increasing the ER folding capacity. However, under prolonged ER stress, UPR can also induce apoptotic cell death. Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus–host interaction. Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP) kinase activation, autophagy, apoptosis, and innate immune response. ER stress and UPR activation may therefore contribute significantly to the viral replication and pathogenesis during coronavirus infection. In this review, we summarize the current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.
Coronaviruses constitute human and animal pathogens that are medically and economically important. Much remains unknown regarding the host–virus interactions during infection. Recent studies have demonstrated that coronaviruse infection induces ER stress in infected cells and activates the UPR. Activation of the PERK pathway (possibly in synergy with PKR and/or other integrated stress response kinases) leads to phosphorylation of eIF2α and a global translation shutdown. At late stage of infection, up-regulation of transcription factor GADD153 likely contributes to coronaviruses induced apoptosis. Activation of the IRE1 pathway induces XBP1 mRNA splicing and expression of downstream UPR genes. Interestingly, IRE1 but not XBP1 is also shown to modulate the JNK and Akt kinase activities, thus protecting infected cells from virus induced apoptosis. The ATF6 pathway is also activated in coronavirus-infected cells, resulting in the up-regulation of chaperon proteins to counteract ER stress.
However, many questions remain to be addressed. First, although the coronaviruses spike proteins are demonstrated to induce ER stress and UPR, detailed mechanisms regarding molecular interactions between the spike proteins and PERK/IRE1/ATF6 have not been determined. Second, it should be noted that the phenotypes observed in cells overexpressing viral proteins may not essentially reflect their physiological functions in the setting of a real infection. Further experiments using recombinant viruses with deletion of or modification in the target viral proteins should be performed to validate these findings (DeDiego et al., 2011). Last but not the least, the three branches of UPR should not be considered functionally independent, but rather as an integrated regulatory network (Ron and Walter, 2007). For example, besides being spliced by IRE1, XBP1 is also transcriptionally activated by PERK and ATF6 (Yoshida et al., 2001a;Calfon et al., 2002). Also, it is difficult to separate the translation shutdown effect mediated by PERK and the induction of UPR genes by PERK and the other two ER stress sensors, as in the studies with MHV (Bechill et al., 2008).
Nonetheless, there are scientific and clinical significance for studies on ER stress and UPR induction during infection with coronaviruses and other viruses. As an evolutionarily conserved and well-characterized stress response pathway, it serves as a perfect model to study host–virus interactions and pathogenesis. Moreover, besides apoptosis, UPR has been recently demonstrated to crosstalk with other major cellular signaling pathways, including MAP kinases pathways, autophagy, and innate immune responses (Yoneda et al., 2001;Ogata et al., 2006;Martinon et al., 2010;Hu et al., 2011;Clavarino et al., 2012). Thus, further investigations on coronavirus-induced UPR may also help identifying new targets for antiviral agents and developing more effective vaccines against coronaviruses.
Reference & Source information:https://www.frontiersin.org/
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