TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2.
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.
Institute for Medical Sciences, Ajou University School of Medicine, Suwon, 443-749, Korea.
Joo-Young
JY
Kim
Michael
M
Morgan
Dong-Gun
DG
Kim
Ju-Yeon
JY
Lee
Lang
L
Bai
Yong
Y
Lin
Zheng-Gang
ZG
Liu
You-Sun
YS
Kim
D000818:Animals; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D020690:GTPase-Activating Proteins; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha