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JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-alpha. 2006

Jianhua Wang, and Chuanyu Li, and Yuelong Liu, and Wan Mei, and Shaohua Yu, and Cunren Liu, and Liming Zhang, and Xu Cao, and Robert P Kimberly, and William Grizzle, and Huang-Ge Zhang
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-0007, USA.

Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-alpha stimulation. Here, we show that JAB1 is a critical regulator of the TNF-alpha-mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-alpha-induced apoptosis response, reduction of nuclear factor-kappaB activity, delayed degradation of IkappaB-alpha, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF-alpha to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-alpha stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-alpha can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-kappaB and JNK in RA FLSs.

UI MeSH Term Description Entries
D010447 Peptide Hydrolases Hydrolases that specifically cleave the peptide bonds found in PROTEINS and PEPTIDES. Examples of sub-subclasses for this group include EXOPEPTIDASES and ENDOPEPTIDASES. Peptidase,Peptidases,Peptide Hydrolase,Protease,Proteases,Proteinase,Proteinases,Proteolytic Enzyme,Proteolytic Enzymes,Esteroproteases,Enzyme, Proteolytic,Hydrolase, Peptide
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011499 Protein Processing, Post-Translational Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility. Amino Acid Modification, Post-Translational,Post-Translational Modification,Post-Translational Protein Modification,Posttranslational Modification,Protein Modification, Post-Translational,Amino Acid Modification, Posttranslational,Post-Translational Amino Acid Modification,Post-Translational Modifications,Post-Translational Protein Processing,Posttranslational Amino Acid Modification,Posttranslational Modifications,Posttranslational Protein Processing,Protein Processing, Post Translational,Protein Processing, Posttranslational,Amino Acid Modification, Post Translational,Modification, Post-Translational,Modification, Post-Translational Protein,Modification, Posttranslational,Modifications, Post-Translational,Modifications, Post-Translational Protein,Modifications, Posttranslational,Post Translational Amino Acid Modification,Post Translational Modification,Post Translational Modifications,Post Translational Protein Modification,Post Translational Protein Processing,Post-Translational Protein Modifications,Processing, Post-Translational Protein,Processing, Posttranslational Protein,Protein Modification, Post Translational,Protein Modifications, Post-Translational
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D005347 Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Fibroblast
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000075686 COP9 Signalosome Complex A multiprotein complex that functions as a peptide hydrolase, or isopeptidase to cleave NEDD8 PROTEIN from the CULLIN and UBIQUITIN-PROTEIN LIGASES, controlling the activity of the ligases. It is highly conserved in eukaryotes and typically consists of 8 subunits (CSN 1-8 proteins). The COP9 signalosome was originally identified in plants, where it controls gene transcription in response to light. COP9 Signalosome (CSN),COP9 Signalosome Subunit 1,COP9 Signalosome Subunit 2,COP9 Signalosome Subunit 3,COP9 Signalosome Subunit 4,COP9 Signalosome Subunit 5,COP9 Signalosome Subunit 6,COP9 Signalosome Subunit 7A,COP9 Signalosome Subunit 7B,COP9 Signalosome Subunit 8,COP9 Signalsome,Constitutive Photomorphogenesis 9 Signalosome,Constitutive Photomorphogenesis 9 Signalsome,FUSCA Protein 11,G Protein Pathway Suppressor 1,Sgn3,Signalosome Subunit 3,Signalosome Complex, COP9,Signalsome, COP9,Subunit 3, Signalosome
D001172 Arthritis, Rheumatoid A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated. Rheumatoid Arthritis
D013582 Synovial Fluid The clear, viscous fluid secreted by the SYNOVIAL MEMBRANE. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. Synovia,Fluid, Synovial,Fluids, Synovial,Synovial Fluids
D013583 Synovial Membrane The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes SYNOVIAL FLUID. Synovium,Membrana Synovialis Capsulae Articularis,Membrane, Synovial,Membranes, Synovial,Synovial Membranes

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