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.
Highlights
During viral replication large amounts of viral proteins must be synthesized, folded, and posttranslationally modified
The most conserved branch of the unfolded protein response (UPR) is the signaling pathway activated by the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1)
In this study we identified the first viral IRE1 inhibitor: The murine cytomegalovirus M50 protein, which interacts with IRE1 and induces its degradation
Summary
During viral replication large amounts of viral proteins must be synthesized, folded, and posttranslationally modified. The high levels of viral envelope glycoproteins that are being synthesized during the late phase of the viral life cycle can overwhelm the folding and processing capacity of the ER and cause accumulation of unfolded and misfolded proteins in the ER [2]. The UPR is initiated by three sensor proteins that recognize ER stress: protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). When unfolded and misfolded proteins accumulate in the ER, BiP dissociates from these sensors to perform its chaperone function. If ER stress persists eIF2a initiates expression of activating transcription factor 4 (ATF4), which induces expression of the proapoptotic transcription factor C/EBP-homologous protein (CHOP, known as growth arrest and DNA damage-inducible protein 153).
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