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XIAP介导的IFT88降解破坏肝星状细胞纤毛，以刺激肝星状细胞激活和肝纤维化。

XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis.

作者信息

Hong Renjie, Tan Yanjie, Tian Xiaoyu, Huang Zhenzhou, Wang Jiaying, Ni Hua, Yang Jia, Bu Weiwen, Yang Song, Li Te, Yu Fan, Zhong Weilong, Sun Tao, Wang Xiaohong, Li Dengwen, Liu Min, Yang Yunfan, Zhou Jun

机构信息

Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, 300071, Tianjin, China.

Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, 250014, Jinan, China.

出版信息

EMBO Rep. 2024 Mar;25(3):1055-1074. doi: 10.1038/s44319-024-00092-y. Epub 2024 Feb 13.

DOI:10.1038/s44319-024-00092-y
PMID:38351372
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10933415/
Abstract

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-β (TGF-β), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-β-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP-IFT88 axis as a potential therapeutic target for liver fibrosis.

摘要

肝星状细胞（HSCs）的激活在肝纤维化中起关键作用。然而，HSC激活的分子基础仍知之甚少。在此，我们证明静止的HSCs上存在初级纤毛，但在HSC激活时显著丢失，这与纤毛蛋白鞭毛内运输蛋白88（IFT88）水平降低相关。Ift88基因敲除小鼠更易患慢性四氯化碳诱导的肝纤维化。机制研究表明，X连锁凋亡抑制蛋白（XIAP）作为IFT88的E3泛素连接酶发挥作用。促纤维化因子转化生长因子-β（TGF-β）增强XIAP介导的IFT88泛素化，促进其蛋白酶体降解。阻断XIAP介导的IFT88降解可消除TGF-β诱导的HSC激活和肝纤维化。这些发现揭示了纤毛稳态在调节HSC激活中的一个以前未被认识的作用，并确定XIAP-IFT88轴是肝纤维化的一个潜在治疗靶点。

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