Paramyxovirus replication induces the hexosamine biosynthetic pathway and mesenchymal transition via the IRE1a-XBP1s arm of the unfolded protein response

Dianhua Qiao, Melissa Skibba, Xiaofang Xu, Roberto P. Garofalo, Yingxin Zhao, Allan R. Brasier

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The paramyxoviridae, respiratory syncytial virus (RSV), and murine respirovirus are enveloped, negative-sense RNA viruses that are the etiological agents of vertebrate lower respiratory tract infections (LRTIs). We observed that RSV infection in human small airway epithelial cells induced accumulation of glycosylated proteins within the endoplasmic reticulum (ER), increased glutaminefructose-6-phosphate transaminases (GFPT1/2) and accumulation of uridine diphosphate (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 unfolded protein response (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), extracellular matrix (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 superenhancer of glutamine-fructose-6-phosphate transaminase 2 (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 on its natural host (mouse). Murine respirovirus induces mucosal growth factor response, EMT, and the indicators of ECM remodeling in an IRE1a-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.

Original languageEnglish (US)
Pages (from-to)L576-L594
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume321
Issue number3
DOIs
StatePublished - Sep 2021

Keywords

  • Epithelial mesenchymal transition
  • Hexosamine biosynthetic pathway
  • N-glycosylation
  • Paramyxovirus
  • Unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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