Paramyxovirus replication induces the Hexosamine Biosynthetic Pathway and Mesenchymal Transition via the IRE1a-XBP1s arm of the Unfolded Protein Response.

Abstract

The paramyoxviridae, Respiratory Syncytial Virus (RSV) and murine respirovirus are enveloped, negative-sense RNA viruses that are the etiological agents of vertebrate respiratory tract infections (LRTIs). We observe RSV infection in human small airway epithelial cells induces accumulation of glycosylated proteins within the ER, increased Glutamine-Fructose-6-Phosphate Transaminases (GFPT1/2), and accumulation of UDP-N-acetylglucosamine, indicating activation of the hexosamine biosynthetic pathway (HBP). RSV infection induces rapid formation of spliced X-box binding protein 1 (XBP1s) and processing of activating transcription factor 6 (ATF6). Using pathway selective inhibitors and shRNA silencing, we find that the inositol requiring enzyme (IRE1a)-XBP1 arm of the UPR is required not only for activation of the HBP, but also for expression of mesenchymal transition (EMT) through the Snail family transcriptional repressor 1 (SNAI1), ECM-remodeling proteins fibronectin (FN1) and matrix metalloproteinase 9 (MMP9). Probing RSV-induced open chromatin domains by ChIP, we find XBP1 binds and recruits RNA Polymerase II to the IL6, SNAI1 and MMP9 promoters and the intragenic super-enhancer of GFPT2. The UPR is sustained through RSV by an autoregulatory loop where XBP1 enhances Pol II binding to its own promoter. Similarly, we investigated the effects of murine respirovirus infection its natural host (mouse). Murine respirovirus induces mucosal growth factor response, EMT and the indicators of ECM remodeling in an IRE1α-dependent manner, which persists after viral clearance. These data suggest that IRE1a-XBP1s arm of the UPR pathway is responsible for paramyxovirus-induced metabolic adaptation and mucosal remodeling via EMT and ECM secretion.