Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Abstract

Protein folding in the endoplasmic reticulum (ER) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the ER, the unfolded protein response (UPR) is triggered as a consequence of ER stress. Due to the secretory function of epithelial cells, UPR plays an important role in maintaining epithelial barrier function at mucosal sites. ER stress and activation of the UPR are natural mechanisms by which mucosal epithelial cells combat viral infections. In this review, we discuss the important role of UPR in regulating mucosal epithelium homeostasis. In addition, we review current insights into how the UPR is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation.

Keywords: endoplasmic reticulum stress; epithelial cells; mucosal barrier; unfolded protein response; viral infection.

Figure 1

Unfolded protein response. During ER stress, the stress sensors dissociate from GRP78 and transduce signals. Cleaved ATF6 translocates to the nucleus to regulate the expressions of UPR target genes. Activation of IRE1 leads to its phosphorylation and oligomerisation, which induces translation of spliced XBP1 to facilitate protein folding, while long‐term IRE1 activation stimulates RIDD signalling to decrease ER protein folding load. Finally, activation of PERK pathway decreases ER protein load by initiating global translational inhibition through eIF2α. ATF4 gene can escape from the translational suppression and translocate to the nucleus to control expressions of UPR target genes. Moreover, prolonged activation of UPR leads to the expressions of inflammatory genes as shown by the dotted arrows.

Figure 2

Inappropriate activation of stress cycle. Although the production of cytokines such as interferons (type I) is beneficial for anti‐viral responses; however, prolonged production further induces protein misfolding and leads to a cycle of stress and inflammation in the absence of pathogens. These sequential events destroy the epithelial integrity and leave the epithelium vulnerable to other chronic diseases. Therefore, stress‐reducing cytokines such as IL‐10 can play an important role to minimise protein misfolding and stop stress–inflammation cycle.

Figure 3

ER stress in mucosal nematode infection. C57BL/6 mice infected with Trichuris muris (T_H1‐dominant: 15 eggs) or (T_H2‐dominant and innate: 150 eggs). (a) Periodic acid–Schiff staining shows increased protein load within goblet cells, and black arrows indicate the worms. (b) Caecal epithelial cell qRT‐PCR shows increased ER stress (sXbp1) in T_H1 and negligible ER stress in T_H2‐dominated immune response, despite an increase in (c) protein load (Muc2). Immunodeficient mice (innate) show no ER stress despite chronic infection and high protein load. Statistics: n = 4–6; ANOVA, ***P < 0.001 vs uninfected (N) mice.

Figure 4

Virus‐controlled UPR response. In homeostatic conditions, proteins are correctly folded in the ER and secreted from cells. However, ER protein misfolding activates UPR pathways leading to the degradation of misfolded proteins, autophagy, inflammation and apoptosis. Viruses can directly or indirectly affect the UPR by selective activation or inhibition of UPR components (shown with red arrows) through endosomal and cytosolic PRRs. Viral‐controlled UPR pathways then ultimately boost the production of viral proteins, while dampening the immune response against the virus.

Figure 5

Proposed mechanism of anti‐viral function of cytokines. Pre‐infection: Basal level of UPR maintains the homeostasis of secretory cell function. Infection: Host ER stress and UPR are intrinsic mechanisms that will limit viral protein synthesis. However, viruses can potentially bypass these mechanisms to replicate. Specific cytokines (such as type I IFNs) that induce oxidative stress would lead to protein misfolding which will be beneficial in limiting viral infection. Post‐infection: Following viral clearance, the wound healing pathways are activated. Specific cytokines, such as IL‐10, known to suppress UPR signals and ER stress, will allow the restoration of normal protein production in the cells.