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Endoplasmic reticulum oxidase 1α is critical for collagen secretion from and membrane type 1-matrix metalloproteinase levels in hepatic stellate cells

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/71529

Title: Endoplasmic reticulum oxidase 1α is critical for collagen secretion from and membrane type 1-matrix metalloproteinase levels in hepatic stellate cells
Authors: Fujii, Mizuki Browse this author
Yoneda, Akihiro Browse this author →KAKEN DB
Takei, Norio Browse this author
Sakai-Sawada, Kaori Browse this author
Kosaka, Marina Browse this author
Minomi, Kenjiro Browse this author
Yokoyama, Atsuro Browse this author →KAKEN DB
Tamura, Yasuaki Browse this author →KAKEN DB
Issue Date: 22-Sep-2017
Publisher: American Society for Biochemistry and Molecular Biology (ASBMB)
Journal Title: Journal of Biological Chemistry (JBC)
Volume: 292
Issue: 38
Start Page: 15649
End Page: 15660
Publisher DOI: 10.1074/jbc.M117.783126
Abstract: Upon liver injury, excessive deposition of collagen from activated hepatic stellate cells (HSCs) is a leading cause of liver fibrosis. An understanding of the mechanism by which collagen biosynthesis is regulated in HSCs will provide important clues for practical anti-fibrotic therapy. Endoplasmic reticulum oxidase 1 alpha (ERO1 alpha) functions as an oxidative enzyme of protein disulfide isomerase, which forms intramolecular disulfide bonds of membrane and secreted proteins. However, the role of ERO1 alpha in HSCs remains unclear. Here, we show that ERO1 alpha is expressed and mainly localized in the endoplasmic reticulum in human HSCs. When HSCs were transfected with ERO1 alpha siRNA or an ERO1 alpha shRNA-expressing plasmid, expression of ERO1 alpha was completely silenced. Silencing of ERO1 alpha expression in HSCs markedly suppressed their proliferation but did not induce apoptosis, which was accompanied by impaired secretion of collagen type 1. Silencing of ERO1 alpha expression induced impaired disulfide bond formation and inhibited autophagy via activation of the Akt/mammalian target of rapamycin signaling pathway, resulting in intracellular accumulation of collagen type 1 in HSCs. Furthermore, silencing of ERO1 alpha expression also promoted proteasome-dependent degradation of membrane type 1-matrix metalloproteinase (MT1-MMP), which stimulates cell proliferation through cleavage of secreted collagens. The inhibition of HSC proliferation was reversed by treatment with MT1-MMP-cleaved collagen type 1. The results suggest that ERO1 alpha plays a crucial role in HSC proliferation via posttranslational modification of collagen and MT1-MMP and, therefore, may be a suitable therapeutic target for managing liver fibrosis.
Rights: This research was originally published in the Journal of Biological Chemistry. Mizuki Fujii, Akihiro Yoneda, Norio Takei, Kaori Sakai-Sawada, Marina Kosaka, Kenjiro Minomi, Atsuro Yokoyama, Yasuaki Tamura. Endoplasmic reticulum oxidase 1α is critical for collagen secretion from and membrane type 1-matrix metalloproteinase levels in hepatic stellate cells. J. Biol. Chem. 2017; 292(38):15649-15660. © the American Society for Biochemistry and Molecular Biology
Type: article
URI: http://hdl.handle.net/2115/71529
Appears in Collections:産学推進本部 (Center for Innovation and business Promotion) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 米田 明弘

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