| First Author | Hong R | Year | 2024 |
| Journal | EMBO Rep | Volume | 25 |
| Issue | 3 | Pages | 1055-1074 |
| PubMed ID | 38351372 | Mgi Jnum | J:360925 |
| Mgi Id | MGI:7614200 | Doi | 10.1038/s44319-024-00092-y |
| Citation | Hong R, et al. (2024) XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis. EMBO Rep 25(3):1055-1074 |
| abstractText | 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-beta (TGF-beta), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-beta-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. |
