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

Wang, Ran; Moniruzzaman, Md.; Shuffle, Eric; Lourie, Rohan; Hasnain, Sumaira Z

The endoplasmic reticulum (ER) is a network of branching tubules that extends throughout the cytoplasm of the cell and serves multiple functions. Once protein is translated by ERassociated ribosomes, it enters into the ER lumen and is folded in a chaperon-assisted manner. Additional complex modifications occur before the protein is transported to Golgi. Appropriate protein folding and post-translational modification are crucial for protein function. Aggregated misfolded proteins in the ER cause cellular stress, which if unresolved can lead to cell death. Despite the stringent regulation around protein folding and redundancy within the chaperone-assisted folding process, both endogenous and exogenous triggers can disrupt the ER homeostasis and increase protein misfolding. These triggers include but are not limited to nutrient deprivation, hypoxia and disruption by chemical inhibitors of polypeptide N-linked glycosylation (e.g. tunicamycin) or calcium flux (e.g. thapsigargin), oxidative stress and infection. As a result, the ER has evolved a regulatory network, known as the unfolded protein response (UPR), to control the protein folding process. The UPR activation involves three major downstream effects including reduction in protein synthesis to reduce ER load, enhancement of ER protein folding capacity and upregulation of ER-associated protein degradation (ERAD). If homeostasis is not regained, the UPR will redirect the balance of signalling to favor autophagy or apoptosis. It is increasingly recognised that the evolutionary conserved UPR signalling has an important role in mucosal inflammation and infection. In this review, we discuss the role of the UPR in maintaining mucosal epithelial cell integrity and barrier function and highlight how the UPR is regulated by the host innate immunity.