Modulation of the Unfolded Protein Response by Viruses: Mechanistic Insights and Implications for viral Pathogenesis.

Abstract

The endoplasmic reticulum (ER) is essential for protein synthesis, folding, maturation, transport, and calcium storage in mammalian cells. Perturbations in ER homeostasis, caused by stressors such as hypoxia, oxidative stress, or infection result in the accumulation of unfolded or misfolded proteins, triggering ER stress. To restore equilibrium, cells activate the unfolded protein response (UPR), a conserved adaptive mechanism mediated by three major ER transmembrane anchored stress sensors: IRE1, PERK, and ATF6. These sensors coordinate translational attenuation, chaperone upregulation, protein degradation, and lipid synthesis to mitigate ER stress and sustain cell survival. However, chronic or dysregulation UPR can induce apoptosis, inflammation, or autophagy. Viruses exploit ER stress and UPR pathway to promote their replication, immune evasion, and persistent infection, highlighting the dual role of the UPR in both host defense and viral survival. A comprehensive understanding of viral modulation of the UPR may reveal novel therapeutic opportunities, offering potential antiviral strategies by targeting host stress response pathways. This review explores how viruses use the UPR to control cell stress and metabolic pathways, and thereby enhance replication and progeny formation, or undergo cell death.