FRI0513 HISTONE-ACETYLTRANSFERASES CBP AND P300 REGULATE AUTOPHAGY AND PROTEASOMAL DEGRADATION IN SYNOVIAL FIBROBLASTS

Abstract

Background Proteasomal degradation and autophagy are the major catabolic pathways that maintain the homeostasis of cells and are associated with cell survival. The histone acetyltransferases cAMP-response element binding protein binding protein (CBP) and p300 are close homologues and widely accepted as redundant proteins. Objectives To analyse individual functions of CBP and p300 in catabolic pathways in rheumatoid arthritis (RA) synovial fibroblasts (SF). Methods SF were isolated from knee, shoulder and hand joints of RA patients undergoing joint replacement surgery. The expression of CBP and p300 was silenced by transfection of antisense LNA gapmeRs (12,5 nM). 24h after transfection cells were stimulated with TNF-α (10 ng/ml, 24h). Transcriptomes were determined by RNA-seq (Illumina NovaSeq 6000, n=6). Pathway enrichment analysis of RNA-seq data (fold change >1.5, FDR Results The top pathway identified after silencing of p300 in SF in presence (p=1.33x10-10) and absence of TNF-α (p=1.76x10-10) was ‘proteasome’, with an enrichment of genes contributing to ‘proteasome assembly’ and ‘proteasome regulation’. The expression of several genes encoding proteasome subunits was increased after p300 silencing but unaffected by silencing of CBP. Genes contributing to the biological processes ‘autophagy’ (p Conclusion Here we identified p300 as a major regulator of the proteasome in SF and provide first evidence for individual functions of CBP and p300 in regulating autophagy in SF. Disclosure of Interests Monika Krosel: None declared, Marcel Gabathuler: None declared, Christoph Kolling: None declared, Matija Tomsic: None declared, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Caroline Ospelt: None declared, Kerstin Klein: None declared