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

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

  • EMBO Rep. 2024 Feb 13. doi: 10.1038/s44319-024-00092-y.
Renjie Hong # 1,  Yanjie Tan # 2,  Xiaoyu Tian # 2,  Zhenzhou Huang 2,  Jiaying Wang 2,  Hua Ni 1,  Jia Yang 1,  Weiwen Bu 1,  Song Yang 1,  Te Li 1,  Fan Yu 1,  Weilong Zhong 3,  Tao Sun 4,  Xiaohong Wang 5,  Dengwen Li 1,  Min Liu 1,  Yunfan Yang 6,  Jun Zhou 7 8
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 300052, Tianjin, China.
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 300071, Tianjin, China.
  • 5 Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 6 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China. yunfanyang@sdu.edu.cn.
  • 7 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. junzhou@nankai.edu.cn.
  • 8 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. junzhou@nankai.edu.cn.
  • # Contributed equally.
PMID: 38351372 DOI: 10.1038/s44319-024-00092-y
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.

Keywords

Cilium; Hepatic Stellate Cell; Liver Fibrosis; Proteasomal Degradation; Ubiquitination.

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