Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms.

Autor: Drinane MC; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Yaqoob U; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Yu H; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Beijing Youan Hospital, Capital Medical University, Beijing, China., Luo F; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Medical College, Xiamen University, Xiamen, Fujian, China., Greuter T; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Arab JP; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Kostallari E; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Verma VK; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Maiers J; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., De Assuncao TM; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Simons M; Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut, USA., Mukhopadhyay D; Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA., Kisseleva T; Department of Surgery, UCSD, California, USA., Brenner DA; Department of Surgery, UCSD, California, USA., Urrutia R; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Lomberk G; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Gao Y; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Ligresti G; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Tschumperlin DJ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Revzin A; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA., Cao S; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Shah VH; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2017 Dec 21; Vol. 2 (24). Date of Electronic Publication: 2017 Dec 21.
DOI: 10.1172/jci.insight.92821
Abstrakt: The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.
Databáze: MEDLINE