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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis* / drug effects
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Arthritis, Rheumatoid / metabolism*
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Arthritis, Rheumatoid / pathology
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COP9 Signalosome Complex
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / metabolism*
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MAP Kinase Kinase 4 / metabolism
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Matrix Metalloproteinases / metabolism
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NF-kappa B / metabolism
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Peptide Hydrolases / metabolism*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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RNA, Small Interfering / pharmacology
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Signal Transduction / drug effects
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Synovial Fluid / metabolism
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Synovial Membrane / metabolism*
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Synovial Membrane / pathology
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TNF Receptor-Associated Factor 2 / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitin / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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RNA, Small Interfering
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Receptors, Tumor Necrosis Factor, Type I
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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Ubiquitin
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MAP Kinase Kinase 4
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Peptide Hydrolases
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COPS5 protein, human
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COP9 Signalosome Complex
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Matrix Metalloproteinases