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

nal mucosal epithelial cells, lung epithelial cells have developed many defence mechanisms to deal with environmental exposures. Increasing evidence shows that the UPR pathways interact with the recognition and handling of exogenous threats, like viruses. 44 The continuous epithelium in the airways acts as a physical barrier to keep the underlying immune system separated from exogenous air-borne pathogens. Ciliated cells continuously clear inhaled matter trapped by the mucus layer. Respiratory goblet cells synthesise and secrete the mucins, MUC5B and MUC5AC rather than MUC2. MUC5B/AC, and their glycoforms contribute to the elasticity and viscous nature of the mucus layer covering epithelium. 45 Mice with Muc5b deficiency develop spontaneous pulmonary pathology from chronic bacterial infection. 46 Distinctive to MUC5B, production of MUC5AC is often associated with pathogenesis of respiratory diseases such as asthma or lung fibrosis. In human bronchial epithelial cells (HBECs), sXBP1 induced ER expansion and Ca 2+ storage contributes to IL-8 secretion. 47 IRE1b is expressed in HBECs and is upregulated in cystic fibrosis and asthmatic HBECs. Studies with Ern2 À/À mice revealed that IRE1b is required for airway mucin production via the activation of the transcription factor XBP1. 48 In response to ER stress, IRE1b activates its endonuclease activity to repress translation through 28S ribosomal RNA cleavage. IRE1b is abundantly expressed in HBECs; 49 hence, the IRE1b-dependent mRNA degradation may be important for efficient translational repression in combating ER stress.