Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

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.

The PERK Arm of the Unfolded Protein Response Negatively Regulates Transmissible Gastroenteritis Virus Replication by Suppressing Protein Translation and Promoting Type I Interferon Production

“…Among the three UPR signaling pathways, PERK is a key molecule that alleviates the accumulation of misfolded proteins in the ER by phosphorylating eIF2␣, which attenuates mRNA translation under ER stress via inhibition of the recycling of eIF2␣ to its active GTP-bound form and blocking the initiation phase of polypeptide chain synthesis (2). We detected a gradual induction of PERK phosphorylation starting at 6 h following TGEV infection or in cells treated with Tu compared to mock-infected cells (Fig.…”

“…Phosphorylation of eIF2␣ decreases translation of most mRNAs by impeding the recycling of eIF2␣ to its active GTP-bound form and inhibiting the delivery of the initiator Met-tRNAi to the initiation complex, allowing cells to conserve resources and to effectively restore homeostasis in the ER (9). The replication of coronaviruses, a family of important animal and human pathogens, is structurally and functionally associated with the ER (2,10,11). During coronavirus infection, several viral proteins are synthesized in the ER (12,13).…”

Identification of N-linked glycosylation sites in the spike protein and their functional impact on the replication and infectivity of coronavirus infectious bronchitis virus in cell culture

“…During coronavirus infection, the massive production of major structural proteins, in particular the large and heavily glycosylated spike protein, has been shown to impose enormous burden to the protein synthetic machinery of ER, leading to the ER stress and induction of unfolded protein response (UPR) (Fung et al, 2014a(Fung et al, , 2016. In fact, overexpression of the S protein of SARS-CoV and MHV induces potent ER stress in cell culture (Chan et al, 2006;Versteeg et al, 2007), while one or more of the three UPR branches are activated in cells infected with SARS-CoV, MHV, TGEV and IBV (Fung et al, 2014b;Fung and Liu, 2014;Liao et al, 2013).…”

Effects of hypervariable regions in spike protein on pathogenicity, tropism, and serotypes of infectious bronchitis virus

“…56.64/referencegene.php). The viral mRNA levels of all the samples were calculated by using the most stably expressed genes as an internal reference for normalization (Fung et al, 2014). The real-time RT-PCR results were expressed as the relative viral load adsorbed or internalized into cells relative to the Beaudette control.…”