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J Cell Sci. 2011 Feb 15;124(Pt 4):647-56. doi: 10.1242/jcs.075770. Epub 2011 Jan 25.

TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2.

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1
Institute for Medical Sciences, Ajou University School of Medicine, Suwon, 443-749, Korea.

Abstract

The current paradigm of noncanonical NF-κB signaling suggests that the loss of TRAF2, TRAF3 or cIAP1 and cIAP2 leads to stabilization of NF-κB-inducing kinase (NIK) to activate the noncanonical pathway. Although a crucial role of RIP1 in the TNFα-induced canonical NF-κB pathway has been well established, its involvement in noncanonical activation of NF-κB through the TNFR1 receptor, is unknown. Here we show that TNFα is capable of activating the noncanonical NF-κB pathway, but that activation of this pathway is negatively regulated by RIP1. In the absence of RIP1, TNFR1 stimulation leads to activation of the noncanonical NF-κB pathway through TRAF2 degradation, leading to NIK stabilization, IKKα phosphorylation and the processing of p100 to generate p52. Thus although RIP1(-/-) mouse embryonic fibroblasts are sensitive at early time points to cell death induced by TNFα, probably as a result of lack of canonical NF-κB activation, the late activation of the noncanonical NF-κB pathway protects the remaining cells from further cell death. The TNFR1-dependent noncanonical NF-κB activation in RIP1(-/-) cells suggests that there is functional interplay between the two NF-κB pathways during TNFR1 signaling, which might regulate the number and kinds of NF-κB transcription factors and thus finely control NF-κB-dependent gene transcription.

PMID:
21266470
DOI:
10.1242/jcs.075770
[Indexed for MEDLINE]
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