Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms. JCI Insight 2017 Dec 21;2(24)
Date
12/22/2017Pubmed ID
29263300Pubmed Central ID
PMC5752303DOI
10.1172/jci.insight.92821Scopus ID
2-s2.0-85050938173 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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.
Author List
Drinane MC, Yaqoob U, Yu H, Luo F, Greuter T, Arab JP, Kostallari E, Verma VK, Maiers J, De Assuncao TM, Simons M, Mukhopadhyay D, Kisseleva T, Brenner DA, Urrutia R, Lomberk G, Gao Y, Ligresti G, Tschumperlin DJ, Revzin A, Cao S, Shah VHAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinThiago Milech De Assuncao Research Scientist II in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Autophagy
Cell Movement
Down-Regulation
Gene Knockdown Techniques
Hepatic Stellate Cells
Humans
Liver Cirrhosis
Mice, Knockout
Pulmonary Fibrosis
Receptors, Platelet-Derived Growth Factor
Ubiquitin
Up-Regulation
