Title: Synectin Promotes Fibrogenesis by Regulating PDGFR Isoforms Through Distinct Mechanisms

Accession Number: GSE93629

Link to Dataset: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE93629

Repository: Gene Expression Omnibus (GEO)

Data Type(s): Gene Expression

Experiment Type(s): Expression profiling by high throughput sequencing

Organism(s): Homo sapiens

Summary: The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As the platelet derived growth factor receptor (PDGFR) pathway is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway in HSC. To study the role of synectin in the development of liver fibrosis, mice with selective deletion of synectin from HSC were generated and found to be protected from fibrosis. RNAseq revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes including PDGFR-β, but not PDGFR-α. Chromatin Immunoprecipitation assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300. In contradistinction, synectin was found to regulate PDGFR-α through an alternative mechanism: protection from autophagic degradation. Site directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF dependent proliferation and migration after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin expression. This work provides insight into differential transcriptional and post-translational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Publication(s) associated with this dataset:

• 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 VH. 2017. Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms. JCI Insight 2(24):92821. doi:10.1172/jci.insight.92821 PMID:29263300 PMCID:PMC5752303