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

Autophagy maintains cellular homeostasis and is involved in MHC class I and II presentation of cytoplasmic and nuclear antigens, which we have reviewed previously. 8 In response to irreversible ER stress, the terminal UPR can activate 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 eIF2a. 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. autophagy to break down the terminally misfolded proteins. During the autophagy process, cellular components are encapsulated within autophagosomes and directed for controlled degradation. Different UPR branches can signal through and induce autophagy, including PERK-eIF2a as well as IRE1a pathways (Figure 1 ). Transcription factor ATF4 that escapes PERKassociated translation inhibition activates transcription of CHOP in cells experiencing persistent ER stress. 5 ATF4 and CHOP can form a heterodimer to activate cellular death pathways and induce expression of a large array of autophagy-related genes. 9 Defects in the UPR and autophagy pathways have synergistic effects. XBP1 is crucial in autophagy induction in some settings, for instance protection from neural degeneration. 10 XBP1 deletion induces only mild superficial intestinal inflammation; however, concomitant deletion of XBP1 and epithelial-associated autophagy-related protein 7 (ATG7) or ATG16L1 results in more severe ER stress and small intestinal inflammation. 11 Supporting this, human genome wide association studies (GWAS) reveal that polymorphisms in ATG16L1 gene and defects in autophagy pathways are associated with increased risk of developing Crohn's disease, a form of inflammatory bowel disease leading to chronic inflammation. 12 Autophagy may also be a mechanism of disposing terminally damaged ER. It was thought to be a non-specific process, but selective autophagy processes that target specific organelles such as mitochondria have been described. Autophagy of ER in mammalian cells was reported, but detailed mechanisms are still unknown. FAM134B, the selective autophagy receptor for ER turnover, induces selective autophagy of the ER (termed ER-phagy) in mammalian cells. 13 It has been suggested that FAM134B binds to microtubule-associated protein 1A/1B-light chain 3 (LC3) and GABA type A receptor-associated protein (GABARAP), thereby initiating ER degradation through autophagy. 13