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

Jianhua Wang, Chuanyu Li, Yuelong Liu, Mei Wan, Shaohua Yu, Cunren Liu, Liming Zhang, Xu Cao, Robert P. Kimberly, William Grizzle, Huang Ge Zhang

Research output: Contribution to journalArticle

Abstract

Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-α stimulation. Here, we show that JAB1 is a critical regulator of the TNF-α-mediated anti-apoptosis pathways in RA FLSs. We found that knock-down of JAB1 using small interfering (si)RNA led to restoration of the TNF-α-induced apoptosis response, reduction of nuclear factor-κB activity, delayed degradation of IκB-α, 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-α 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-α 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-α can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-κB and JNK in RA FLSs.

Original languageEnglish (US)
Pages (from-to)889-902
Number of pages14
JournalAmerican Journal of Pathology
Volume169
Issue number3
DOIs
StatePublished - Sep 2006
Externally publishedYes

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TNF Receptor-Associated Factor 2
Rheumatoid Arthritis
Tumor Necrosis Factor-alpha
Fibroblasts
Ubiquitination
Apoptosis
Small Interfering RNA
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Polyubiquitin
Receptors, Tumor Necrosis Factor, Type I
Tumor Necrosis Factor Receptors
Matrix Metalloproteinases
Immunoprecipitation
Confocal Microscopy
Lysine
Phosphorylation
Synoviocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-α. / Wang, Jianhua; Li, Chuanyu; Liu, Yuelong; Wan, Mei; Yu, Shaohua; Liu, Cunren; Zhang, Liming; Cao, Xu; Kimberly, Robert P.; Grizzle, William; Zhang, Huang Ge.

In: American Journal of Pathology, Vol. 169, No. 3, 09.2006, p. 889-902.

Research output: Contribution to journalArticle

Wang, J, Li, C, Liu, Y, Wan, M, Yu, S, Liu, C, Zhang, L, Cao, X, Kimberly, RP, Grizzle, W & Zhang, HG 2006, 'JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-α', American Journal of Pathology, vol. 169, no. 3, pp. 889-902. https://doi.org/10.2353/ajpath.2006.051161
Wang, Jianhua ; Li, Chuanyu ; Liu, Yuelong ; Wan, Mei ; Yu, Shaohua ; Liu, Cunren ; Zhang, Liming ; Cao, Xu ; Kimberly, Robert P. ; Grizzle, William ; Zhang, Huang Ge. / JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-α. In: American Journal of Pathology. 2006 ; Vol. 169, No. 3. pp. 889-902.
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