The RING Domain of TRAF2 Plays an Essential Role in the Inhibition of TNFα-Induced Cell Death but Not in the Activation of NF-κB

JOURNAL OF MOLECULAR BIOLOGY

卷:396

Article

Zhang, Laiqun¹  Blackwell, Ken¹  Shi, Zhaohui¹  Habelhah, Hasem¹ 

[1] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA

关键词: TNF alpha;    TRAF2;    JNK;    NF-kappa B;    apoptosis;   

DOI  :  10.1016/j.jmb.2010.01.008

来源: Elsevier

【 摘 要 】

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and receptor-interacting protein I (RIP1) play critical roles in activating c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase (IKK), as well as in inhibiting apoptosis induced by TNF alpha. The TRAF2 RING domain-mediated polyubiquitination of RIP1 is believed to be essential for TNF alpha-induced IKK activation, and the RING-domain-deleted TRAF2 (TRAF2-Delta R) has been widely used as a dominant negative in transient overexpression systems to block TNF alpha-induced JNK and IKK activation. Here, we report that stable expression of TRAF2-Delta R at a physiological level in TRAF2 and TRAF5 double knockout (TRAF2/5 DKO) cells almost completely restores normal TNF alpha-induced IKK activation, but not RIP1 polyubiquitination. In addition, stable expression of TRAF2-Delta R in TRAF2/5 DKO cells efficiently inhibited the TNF alpha-induced later phase of prolonged JNK activation, yet failed to inhibit TNF alpha-induced cell death. Although the basal and inducible expression of anti-apoptotic proteins in TRAF2-Delta R-expressing TRAF2/5 DKO cells was normal, the cells remained sensitive to TNF alpha-induced cell death because anti-apoptotic proteins were not recruited to the TNFR1 complex efficiently. Moreover, stable expression of TRAF2-Delta R in TRAF2/5 DKO cells failed to suppress constitutive p100 processing in these cells. These data suggest that (i) the TRAF2 RING domain plays a critical role in inhibiting cell death induced by TNF alpha and is essential for suppressing the noncanonical nuclear factor kappa B pathway in unstimulated cells; (ii) RIP1 polyubiquitination is not essential for TNF alpha-induced IKK activation; and (iii) prolonged JNK activation has no obligate role in TNF alpha-induced cell death. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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