Fig. 1.

Signaling pathways of three branches of UPR and modulations by coronavirus infection. (A) Coronavirus replication causes ER stress by three major mechanisms. The ER stress sensors PERK, IRE1, and ATF6 are activated and trigger UPR in an attempt to counter ER stress. (B) The signaling pathway of integrated stress response and coronavirus intervention. Infection with MHV-A59, SARS-CoV, and IBV has been shown to cause eIF2α phosphorylation, which is most likely mediated by PKR and/or PERK. The phosphorylated eIF2α sequesters eIF2B, inhibits recycling of GTP-bound eIF2α and leads to translation attenuation. (C) The IRE1 signaling pathway and coronavirus intervention. IRE1 mediates splicing of XBP1, which induces UPR genes such as ERdj4 and p58^IPK. IRE1 can also recruit TRAF2 and activate JNK-mediated apoptosis. The over-expression of spike proteins of IBV and MHV-A59 has been shown to activate IRE1, whereas the SARS-CoV E protein inhibits XBP1 splicing. (D) The ATF6 signaling pathway and coronavirus intervention. ATF6 protein is cleaved by S1P and S2P under ER stress. The released fragment (ATF6f) translocates to the nucleus and induces UPR genes. Transfection of SARS-CoV accessory protein 8ab or infection with IBV or MHV-A59 has been shown to induce ATF6 cleavage.