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 activation of NFjB, key regulator for immunity and inflammatory response, is linked to the UPR. The NFjB inhibitor IjB has a shorter halflife than NFjB: activation of PERK and concomitant translational inhibition through eIF2a leads to NFjB activation independent of IjB phosphorylation. 16 Also, IRE1a can interact with TNF receptor activating factor 2, which recruits IjB kinase leading to IjB phosphorylation and NFjB activation. 17 It is important to note that ER stress and the UPR have been reported to influence NFjB activation both positively and negatively ( Figure 1 ). The intensity of ER stress influences NFjB activation status positively; 18 however, preconditioning of cells with low level of ER stress is thought to attenuate NFjB activation. 19 Conversely, mucosal inflammation modifies ER stress and UPR pathways. Both ROS and RNS produced by innate immune cells during inflammation can activate the UPR in target cells directly. Inflammatory cytokines such as IL-17A, IFN-c and IL-23 initiate the UPR indirectly via inducing oxidative stress, which inhibits the production of protein disulphide isomerases, that are key components of the endoplasmic reticulumassisted folding system (ERAF), resulting in the accumulation of unfolded proteins within the ER and UPR activation. 20 In contrast, cytokines, like IL-10 and IL-22, have been shown to suppress ER stress and its associated UPR activation to alleviate inflammation in intestinal mucosal system. 21, 22 The evolutionary benefit of the ability of cytokines to rapidly stop/start protein synthesis is unclear, but may relate to cellular defences during viral infection, as discussed later.