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

Academic Article

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.
  • Published In

    Keywords

  • Apoptosis, Arthritis, Rheumatoid, COP9 Signalosome Complex, Cell Proliferation, Cell Survival, Fibroblasts, Humans, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 4, Matrix Metalloproteinases, NF-kappa B, Peptide Hydrolases, Phosphorylation, Protein Processing, Post-Translational, RNA, Small Interfering, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Synovial Fluid, Synovial Membrane, TNF Receptor-Associated Factor 2, Transfection, Tumor Necrosis Factor-alpha, Ubiquitin
  • Author List

  • Wang J; Li C; Liu Y; Mei W; Yu S; Liu C; Zhang L; Cao X; Kimberly RP; Grizzle W
  • Start Page

  • 889
  • End Page

  • 902
  • Volume

  • 169
  • Issue

  • 3