Type II Epithelial-Mesenchymal Transition Upregulates Protein N-Glycosylation to Maintain Proteostasis and Extracellular Matrix Production

Jing Zhang, Mohammad Jamaluddin, Yueqing Zhang, Steven G. Widen, Hong Sun, Allan R. Brasier, Yingxin Zhao

Research output: Contribution to journalArticle

Abstract

Type II epithelial-mesenchymal transition (EMT) plays a vital role in airway injury, repair, and remodeling. Triggered by growth factors, such as transforming growth factor beta (TGFβ), EMT induced a biological process that converts epithelial cells into secretory mesenchymal cells with a substantially increased production of extracellular matrix (ECM) proteins. Epithelial cells are not professional secretory cells and produce few ECM proteins under normal conditions. The molecular mechanism underlying the transformation of the protein factory and secretory machinery during EMT is significant because ECM secretion is central to the pathogenesis of airway remodeling. Here we report that type II EMT upregulates the protein N-glycosylation of ECMs. The mechanism study reveals that the substantial increase in synthesis of ECM proteins in EMT activates the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 (XBP1) axis of the unfolded protein response (UPR) coupled to the hexosamine biosynthesis pathway (HBP). These two pathways coordinately up-regulate the protein N-glycosylation of ECM proteins and increase ER folding capacity and ER-associated degradation (ERAD), which improve ER protein homeostasis and protect transitioned cells from proteotoxicity. Inhibition of the alternative splicing of XBP1 or protein N-glycosylation blocks ECM protein secretion, indicating the XBP1-HBP plays a prominent role in regulating the secretion of ECM proteins in the mesenchymal transition. Our data suggest that the activation of XBP1-HBP pathways and elevation of protein N-glycosylation is an adaptive response to maintain protein quality control and facilitate the secretion of ECM proteins during the mesenchymal transition. The components of the XBP1-HBP pathways may be therapeutic targets to prevent airway remodeling.

Original languageEnglish (US)
Pages (from-to)3447-3460
Number of pages14
JournalJournal of Proteome Research
Volume18
Issue number9
DOIs
StatePublished - Sep 6 2019

Fingerprint

Glycosylation
Epithelial-Mesenchymal Transition
Extracellular Matrix Proteins
Extracellular Matrix
Up-Regulation
Hexosamines
Biosynthesis
Carrier Proteins
Proteins
Airway Remodeling
Epithelial Cells
Biological Phenomena
Unfolded Protein Response
Alternative Splicing
Inositol
Military electronic countermeasures
Transforming Growth Factor beta
Quality Control
Intercellular Signaling Peptides and Proteins
Homeostasis

Keywords

  • and hexosamine biosynthesis pathway
  • epithelial-mesenchymal transition
  • extracellular matrix
  • N-glycosylation
  • proteomics
  • secretome
  • unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Cite this

Type II Epithelial-Mesenchymal Transition Upregulates Protein N-Glycosylation to Maintain Proteostasis and Extracellular Matrix Production. / Zhang, Jing; Jamaluddin, Mohammad; Zhang, Yueqing; Widen, Steven G.; Sun, Hong; Brasier, Allan R.; Zhao, Yingxin.

In: Journal of Proteome Research, Vol. 18, No. 9, 06.09.2019, p. 3447-3460.

Research output: Contribution to journalArticle

Zhang, Jing ; Jamaluddin, Mohammad ; Zhang, Yueqing ; Widen, Steven G. ; Sun, Hong ; Brasier, Allan R. ; Zhao, Yingxin. / Type II Epithelial-Mesenchymal Transition Upregulates Protein N-Glycosylation to Maintain Proteostasis and Extracellular Matrix Production. In: Journal of Proteome Research. 2019 ; Vol. 18, No. 9. pp. 3447-3460.
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AB - Type II epithelial-mesenchymal transition (EMT) plays a vital role in airway injury, repair, and remodeling. Triggered by growth factors, such as transforming growth factor beta (TGFβ), EMT induced a biological process that converts epithelial cells into secretory mesenchymal cells with a substantially increased production of extracellular matrix (ECM) proteins. Epithelial cells are not professional secretory cells and produce few ECM proteins under normal conditions. The molecular mechanism underlying the transformation of the protein factory and secretory machinery during EMT is significant because ECM secretion is central to the pathogenesis of airway remodeling. Here we report that type II EMT upregulates the protein N-glycosylation of ECMs. The mechanism study reveals that the substantial increase in synthesis of ECM proteins in EMT activates the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 (XBP1) axis of the unfolded protein response (UPR) coupled to the hexosamine biosynthesis pathway (HBP). These two pathways coordinately up-regulate the protein N-glycosylation of ECM proteins and increase ER folding capacity and ER-associated degradation (ERAD), which improve ER protein homeostasis and protect transitioned cells from proteotoxicity. Inhibition of the alternative splicing of XBP1 or protein N-glycosylation blocks ECM protein secretion, indicating the XBP1-HBP plays a prominent role in regulating the secretion of ECM proteins in the mesenchymal transition. Our data suggest that the activation of XBP1-HBP pathways and elevation of protein N-glycosylation is an adaptive response to maintain protein quality control and facilitate the secretion of ECM proteins during the mesenchymal transition. The components of the XBP1-HBP pathways may be therapeutic targets to prevent airway remodeling.

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