Flaviviral Regulation of the Unfolded Protein Response: Can Stress be Beneficial?

Members of the Flaviviridae family remain some of the most significant human viral pathogens, with few vaccines or antivirals commercially available for therapeutic use. Thus, understanding the intracellular events of replication and how these viruses modulate signaling within an infected cell is of great importance. The ER is central to replication within the Flaviviridae family, as the site of viral protein translation and processing, as a source of membranes for replication complex formation and as a site of virus assembly. This places a large burden upon the organelle, resulting in the induction of ER stress responses, in particular the unfolded protein response. In turn, unfolded protein response signaling induced in infected cells is tightly modulated by the virus in order to maintain an optimal environment for replication. The loss of various components of the stress response can have either beneficial or detrimental effects, presenting intriguing targets for antiviral discovery.