Cytomegalovirus Downregulates IRE1 to Repress the Unfolded Protein Response

Abstract

During viral infection, a massive demand for viral glycoproteins can overwhelm the capacity of the protein folding and quality control machinery, leading to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). To restore ER homeostasis, cells initiate the unfolded protein response (UPR) by activating three ER-to-nucleus signaling pathways, of which the inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved. To reduce ER stress, the UPR decreases protein synthesis, increases degradation of unfolded proteins, and upregulates chaperone expression to enhance protein folding. Cytomegaloviruses, as other viral pathogens, modulate the UPR to their own advantage. However, the molecular mechanisms and the viral proteins responsible for UPR modulation remained to be identified. In this study, we investigated the modulation of IRE1 signaling by murine cytomegalovirus (MCMV) and found that IRE1-mediated mRNA splicing and expression of the X-box binding protein 1 (XBP1) is repressed in infected cells. By affinity purification, we identified the viral M50 protein as an IRE1-interacting protein. M50 expression in transfected or MCMV-infected cells induced a substantial downregulation of IRE1 protein levels. The N-terminal conserved region of M50 was found to be required for interaction with and downregulation of IRE1. Moreover, UL50, the human cytomegalovirus (HCMV) homolog of M50, affected IRE1 in the same way. Thus we concluded that IRE1 downregulation represents a previously undescribed viral strategy to curb the UPR.

Emerging functions of the unfolded protein response in immunity

“…Furthermore, LPS induces no canonical XBP-1s gene signature, but specifically triggers XBP-1s for optimal cytokine secretion 57 . This has also been observed in the case of HCV, CMV or West Nile virus infection 117, 121, 122 . TLR signaling suppresses the ATF4-CHOP branch by enhancing eIF2B guanine exchange activity and as such counteracting the inhibitory effects of phosphorylated eIF2α on ternary complex formation and protein translation 58, 123 .…”

“…Hepatitis C virus (HCV) triggers the UPR, which in turn activates the autophagic pathway that promotes viral replication 126 . The cytomegalovirus protein M50 specifically constrains IRE1-dependent ERAD pathways by binding to and degrading IRE1 121 . On the other hand, the IRE1 pathway is specifically activated by Japanese encephalitis virus (JEV) and influenza to support viral replication 119, 127 .…”

Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?

“…Induction of the UPR by human CMV protein US11 has been proposed to lead to degradation of MHC Class I, a mechanism that may promote chronic infection 112 . Further, HCMV protein UL50 and its murine CMV homolog M50, can both downregulate IRE1 to suppress the UPR 111 . Hepatitis C virus also downregulates the IRE1-XBP1 pathway to promote viral replication 113,114 .…”

Innate immunity at mucosal surfaces: the IRE1-RIDD-RIG-I pathway

“…Infection by human cytomegalovirus is one recently described example. In this case, the nascent viral membrane protein UL50 binds IRE1α and somehow causes its degradation, thus obfuscating the IRE1α branch of the UPR [94]. But this is not pattern recognition either – a term used here to denote receptor-mediated surveillance for microbes or their products [95].…”