The expanding roles of endoplasmic reticulum stress in virus replication and pathogenesis

Abstract

The endoplasmic reticulum (ER) is a cellular membrane organelle that plays important roles in virus replication and maturation. Accumulating evidence indicates that virus infection often disturbs ER homeostasis and leads to ER stress, which is associated with a variety of prevalent diseases. To cope with the deleterious effects of virus-induced ER stress, cells activate critical signaling pathways including the unfolded protein response (UPR) and intrinsic mitochondrial apoptosis, which have complex effects on virus replication and pathogenesis. In this review, we present a comprehensive summary of recent research in this field, which revealed that about 36 viruses trigger ER stress and differentially activate ER stress-related signaling pathways. We also highlight the strategies evolved by viruses to modulate ER stress-related signaling networks including immune responses in order to ensure their survival and pathogenesis. Together, the knowledge gained from this field will shed light on unveiling the mechanisms of virus replication and pathogenesis and provide insight for future research as well as antiviral development.

Keywords: Antiviral therapy; ER-to-nucleus signaling pathway; apoptosis; unfolded protein response; virological treatments.

Figure 1.

Modulation of the UPR by viruses. In virus-infected cells, three membrane transducers: PERK, ATF6, IRE1 are differentially activated to gain ER homeostasis. Arrows represent activation of the UPR components by virus infection; lines indicate inhibition of the UPR components by virus infection or inhibition between the UPR components.

Figure 2.

Modulation of apoptosis by viruses. Arrows indicate viruses and viral proteins that activate the components of apoptosis; lines indicate viruses and viral proteins that suppress the components of apoptosis; the left bottom box indicates the viruses that induce both ER stress and apoptosis but the causality between these two pathways is unknown; the right bottom box indicates the viruses that induce ER stress but repress apoptosis. HBV induces ER stress-mediated apoptosis but it is unknown which pathway contributes to apoptosis. Cyto c, cytochrome c.