The endoplasmic reticulum unfolded protein response – homeostasis, cell death and evolution in virus infections

Viruses elicit cell and organismic stress, and offset homeostasis. They trigger intrinsic, innate and adaptive immune responses, which limit infection. Viruses restore homeostasis by harnessing evolutionary conserved stress responses, such as the endoplasmic reticulum (ER) unfolded protein response (UPR(ER)). The canonical UPR(ER) restores homeostasis based on a cell-autonomous signalling network modulating transcriptional and translational output. The UPR(ER) remedies cell damage, but upon severe and chronic stress leads to cell death. Signals from the UPR(ER) flow along three branches with distinct stress sensors, the inositol requiring enzyme (Ire) 1, protein kinase R (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). This review shows how both enveloped and non-enveloped viruses use the UPR(ER) to control cell stress and metabolic pathways, and thereby enhance infection and progeny formation, or undergo cell death. We highlight how the Ire1 axis bypasses apoptosis, boosts viral transcription and maintains dormant viral genomes during latency and persistence periods concurrent with long term survival of infected cells. These considerations open new options for oncolytic virus therapies against cancer cells where the UPR(ER) is frequently upregulated. We conclude with a discussion of the evolutionary impact that viruses, in particular retroviruses, and anti-viral defense has on the UPR(ER).