title: JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-alpha.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-0007, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.forename: Chuanyu
authors.initials: C
authors.lastname: Li
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Liu
authors.forename: Wan
authors.initials: W
authors.lastname: Mei
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yu
authors.forename: Cunren
authors.initials: C
authors.lastname: Liu
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: William
authors.initials: W
authors.lastname: Grizzle
authors.forename: Huang-Ge
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D000075686:COP9 Signalosome Complex; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D048670:MAP Kinase Kinase 4; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D020782:Matrix Metalloproteinases