Modification of Nuclear PML Protein by SUMO-1 Regulates Fas-Induced Apoptosis in Rheumatoid Arthritis Synovial Fibroblasts

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-03, Vol.104 (12), p.5073-5078
• Main Authors: Meinecke, Ingmar, Cinski, Antje, Baier, Anja, Peters, Marvin A., Dankbar, Berno, Wille, Aline, Drynda, Andreas, Mendoza, Heidi, Gay, Renate E., Hay, Ronald T., Ink, Barbara, Gay, Steffen, Pap, Thomas
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - secretion; Antibodies; Apoptosis; Apoptosis - drug effects; Arthritis, Rheumatoid - pathology; Biological Sciences; Cell death; Cell nucleus; Cell Nucleus - drug effects; Cell Nucleus - enzymology; Cell Nucleus - metabolism; Cysteine Endopeptidases; Endopeptidases - genetics; Endopeptidases - metabolism; Fas Ligand Protein - pharmacology; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - pathology; Gene Expression - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Humans; Immune system; Immunology; Intranuclear Inclusion Bodies - drug effects; Messenger RNA; Neoplasm Proteins - metabolism; Nuclear Proteins - metabolism; Nuclear Proteins - secretion; Pathology; Physiological regulation; Promyelocytic Leukemia Protein; Protein Processing, Post-Translational - drug effects; Proteins; Rheumatoid arthritis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Small interfering RNA; SUMO-1 Protein - metabolism; Synovial Fluid - cytology; Synovial Fluid - drug effects; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0608773104

The small ubiquitin-like modifier (SUMO)-1 is an important posttranslational regulator of different signaling pathways and involved in the formation of promyelocytic leukemia (PML) protein nuclear bodies (NBs). Overexpression of SUMO-1 has been associated with alterations in apoptosis, but the underlying mechanisms and their relevance for human diseases are not clear. Here, we show that the increased expression of SUMO-1 in rheumatoid arthritis (RA) synovial fibroblasts (SFs) contributes to the resistance of these cells against Fas-induced apoptosis through increased SUMOylation of nuclear PML protein and increased recruitment of the transcriptional repressor DAXX to PML NBs. We also show that the nuclear SUMO-protease SENP1, which is found at lower levels in RA SFs, can revert the apoptosis-inhibiting effects of SUMO-1 by releasing DAXX from PML NBs. Our findings indicate that in RA SFs overexpression of SENP1 can alter the SUMO-1-mediated recruitment of DAXX to PML NBs, thus influencing the proapoptotic effects of DAXX. Accumulation of DAXX in PML NBs by SUMO-1 may, therefore, contribute to the pathogenesis of inflammatory disorders.