title: Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts.
abstract: 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.
authors.affiliation: Department of Traumatology and Reconstructive Surgery, University Hospital Munster, D-48149 Munster, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Meinecke
authors.forename: Antje
authors.initials: A
authors.lastname: Cinski
authors.forename: Anja
authors.initials: A
authors.lastname: Baier
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Peters
authors.forename: Berno
authors.initials: B
authors.lastname: Dankbar
authors.forename: Aline
authors.initials: A
authors.lastname: Wille
authors.forename: Andreas
authors.initials: A
authors.lastname: Drynda
authors.forename: Heidi
authors.initials: H
authors.lastname: Mendoza
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Hay
authors.forename: Barbara
authors.initials: B
authors.lastname: Ink
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D056970:Co-Repressor Proteins; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D053222:Fas Ligand Protein; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases