Insights Into the Role of Endoplasmic Reticulum Stress in Infectious Diseases

Abstract

The endoplasmic reticulum (ER) is the major organelle in the cell for protein folding and plays an important role in cellular functions. The unfolded protein response (UPR) is activated in response to misfolded or unfolded protein accumulation in the ER. However, the UPR successfully alleviates the ER stress. If UPR fails to restore ER homeostasis, apoptosis is induced. ER stress plays an important role in innate immune signaling in response to microorganisms. Dysregulation of UPR signaling contributes to the pathogenesis of a variety of infectious diseases. In this review, we summarize the contribution of ER stress to the innate immune response to invading microorganisms and its role in the pathogenesis of infectious diseases.

Keywords: ER stress; UPR (unfolded protein response); apoptosis; bacteria; infection; infectious disease; pathogen; viruses.

Figure 1

Schematic overview of unfolded protein response (UPR) signaling during bacterial infection. (A) Three ER stress sensors–IRE1, PERK, and ATF6–are activated when the accumulation of misfolded protein aggregates promotes recruitment of BiP. Bacterial infection and toxins activate the UPR. (B) During mycobacterial infection, co-translocated calreticulin and ERp57 form a complex with TNFR1 and CXCR1 in the plasma membrane, leading to apoptosis, and suppression of intracellular Mtb. The interaction of Par-4 and BiP leads to apoptosis by inducing Mtb-mediated ER stress and activating the FADD/caspase-8/-3 pathway. The mycobacterial antigens HBHA and ESAT-6 affect the ER membrane and induce the release of Ca²⁺ from the ER to mitochondria, leading to the production of reactive oxygen species and apoptosis.

Figure 2

Schematic overview of UPR signaling during viral infection. Viral infection induces ER stress and the UPR, which promotes cell survival by inhibiting apoptosis. Some viral infection induces ER-stress-mediated apoptosis by promoting the synthesis of CHOP. IRE1 activates RIDD to promote the degradation of ER-localized mRNAs. The activation of RIDD may enhance viral protein synthesis. The interaction between the UPR pathways and the autophagic response is implicated in the pathogenesis of viral infection.