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

• Fujii, Mizuki

• Yoneda, Akihiro

• Takei, Norio

• Sakai-Sawada, Kaori

• Kosaka, Marina

• Minomi, Kenjiro

• Yokoyama, Atsuro

• Tamura, Yasuaki

抄録

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.

収録刊行物

• Journal of Biological Chemistry (JBC)

  Journal of Biological Chemistry (JBC) 292 (38), 15649-15660, 2017-09-22

  American Society for Biochemistry and Molecular Biology (ASBMB)

詳細情報

• CRID: 1050001339054486656
• NII論文ID: 120006522663
• HANDLE: 2115/71529
• ISSN: 00219258
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles