Type II Epithelial-Mesenchymal
Transition Upregulates
Protein N‑Glycosylation To Maintain Proteostasis and Extracellular
Matrix Production
Posted on 2019-08-27 - 20:46
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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Zhang, Jing; Jamaluddin, Mohammad; Zhang, Yueqing; Widen, Steven G.; Sun, Hong; Brasier, Allan R; et al. (2019). Type II Epithelial-Mesenchymal
Transition Upregulates
Protein N‑Glycosylation To Maintain Proteostasis and Extracellular
Matrix Production. ACS Publications. Collection. https://doi.org/10.1021/acs.jproteome.9b00342
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AUTHORS (7)
JZ
Jing Zhang
MJ
Mohammad Jamaluddin
YZ
Yueqing Zhang
SW
Steven G. Widen
HS
Hong Sun
AB
Allan R Brasier
YZ
Yingxin Zhao
KEYWORDS
ERADconverts epithelial cellsTGFtype II EMT upregulatesIREinositol-requiring protein 1Extracellular Matrix Production Type II epithelial-mesenchymal transitionER protein homeostasisUPRpathways coordinately up-regulateECM proteinsmesenchymal transitionprotein quality controlgrowth factor betaXBP 1-HBP pathwayshexosamine biosynthesis pathwayprotein N-glycosylationsecretory mesenchymal cellsprotein N-glycosylation blocks ECM protein secretion