Journal article
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, Vol.396(3), pp.528-539
02/26/2010
DOI: 10.1016/j.jmb.2010.01.008
PMCID: PMC2822030
PMID: 20064526
Abstract
Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1) play critical roles in activating c-Jun N-terminal kinase (JNK) and inhibitor of κB kinase (IKK), as well as in inhibiting apoptosis induced by TNFα. The TRAF2 RING domain-mediated polyubiquitination of RIP1 is believed to be essential for TNFα-induced IKK activation, and the RING-domain-deleted TRAF2 (TRAF2-ΔR) has been widely used as a dominant negative in transient overexpression systems to block TNFα-induced JNK and IKK activation. Here, we report that stable expression of TRAF2-ΔR at a physiological level in TRAF2 and TRAF5 double knockout (TRAF2/5 DKO) cells almost completely restores normal TNFα-induced IKK activation, but not RIP1 polyubiquitination. In addition, stable expression of TRAF2-ΔR in TRAF2/5 DKO cells efficiently inhibited the TNFα-induced later phase of prolonged JNK activation, yet failed to inhibit TNFα-induced cell death. Although the basal and inducible expression of anti-apoptotic proteins in TRAF2-ΔR-expressing TRAF2/5 DKO cells was normal, the cells remained sensitive to TNFα-induced cell death because anti-apoptotic proteins were not recruited to the TNFR1 complex efficiently. Moreover, stable expression of TRAF2-ΔR 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 TNFα and is essential for suppressing the noncanonical nuclear factor κB pathway in unstimulated cells; (ii) RIP1 polyubiquitination is not essential for TNFα-induced IKK activation; and (iii) prolonged JNK activation has no obligate role in TNFα-induced cell death.
Details
- Title: Subtitle
- 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
- Creators
- Laiqun ZhangKen BlackwellZhaohui ShiHasem Habelhah
- Resource Type
- Journal article
- Publication Details
- Journal of molecular biology, Vol.396(3), pp.528-539
- DOI
- 10.1016/j.jmb.2010.01.008
- PMID
- 20064526
- PMCID
- PMC2822030
- NLM abbreviation
- J Mol Biol
- ISSN
- 0022-2836
- eISSN
- 1089-8638
- Publisher
- Elsevier Ltd
- Grant note
- name: NCI, award: CA78419
- Language
- English
- Date published
- 02/26/2010
- Academic Unit
- Pathology
- Record Identifier
- 9984047783302771
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