Activation and inhibition of the IRE1-mediated unfolded protein response by cytomegalovirus

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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 evolutionary 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 remain poorly defined. In previous work we demonstrated that murine and human cytomegalovirus (MCMV and HCMV) repress IRE1-mediated mRNA splicing and expression of the X-box binding protein 1s (XBP1s) at late times post infection. We identified the MCMV M50 protein as an IRE1-interacting protein that induces proteasomal degradation of IRE1. We further showed that viral infection briefly activates the IRE1-XBP1 signaling pathway. This activation appears to be important as genetic inactivation of IRE1 resulted in a massive reduction of viral replication. Surprisingly, however, XBP1 inactivation caused only a minor decrease in viral productivity. Based on our preliminary data we propose that cytomegaloviruses first activate an IRE-dependent pathway and later block IRE1 signaling by targeting it for degradation. Therefore, the aims of this project is to identify the IRE1-dependent signaling pathway required for efficient viral replication, to determine the mechanism and biological impact of viral induced IRE1 degradation, and to investigate whether the activation and inhibition of IRE1 signaling is conserved among beta- and gamma-herpesviruses. The results will provide a better understanding how viruses manipulate the UPR to their own advantage and might reveal new targets for therapeutic intervention.