Wang Jianhua, Li Chuanyu, Liu Yuelong, Mei Wan, Yu Shaohua, Liu Cunren, Zhang Liming, Cao Xu, Kimberly Robert P, Grizzle William, Zhang Huang-Ge
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-0007, USA.
Am J Pathol. 2006 Sep;169(3):889-902. doi: 10.2353/ajpath.2006.051161.
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.
类风湿关节炎患者的成纤维样滑膜细胞（RA FLSs）对肿瘤坏死因子（TNF）-α刺激表现出促生存而非凋亡反应。在此，我们表明JAB1是RA FLSs中TNF-α介导的抗凋亡途径的关键调节因子。我们发现，使用小干扰（si）RNA敲低JAB1可导致TNF-α诱导的凋亡反应恢复、核因子-κB活性降低、IκB-α降解延迟，并抑制JNK磷酸化。通过相互免疫共沉淀和共聚焦显微镜分析JAB1的相互作用，发现JAB1与TNF受体相关因子2（TRAF2）相互作用。TNF-α与TNF受体（TNFR）1结合时抗凋亡信号的产生已被证明与TRAF2募集到TNFR1有关，这一过程需要TRAF2通过赖氨酸-63连接的多聚泛素链进行泛素化。我们发现，TNF-α刺激JAB1 siRNA转染的RA FLSs未能刺激TRAF2的泛素化。因此，我们得出结论，JAB1调节的TRAF2泛素化是一种新机制，通过该机制TNF-α可通过激活核因子-κB和JNK在RA FLSs中诱导抗凋亡信号和基质金属蛋白酶的产生。
