New Perspectives in TNF-R1-Induced NF-κB Signaling
The ubiquitylation events leading to activation of NF-κB at the TNFR1 receptor have been a topic of intense study. It is believed that K63 ubiquitylation of the kinase RIPK1 is required for recruitment of the TAB2/TAB3/TAK1 and IKK1/IKK2/NEMO complexes that are in turn required to phosphorylate and degrade IκBα allowing freed NF-κB dimers to nuclear translocation. The exact involvement of the E3 ligases, TRAF2, TRAF5, cIAP1, and cIAP2 in this process has been unclear. We summarize a recent study from our lab defining the roles of TRAF2 and cIAP1 s in activation of NF-κB downstream of TNF-R1 and report the surprising finding that RIPK1 is not essential for TNF-R1-induced NF-κB. Alternative mechanisms of how NF-κB may be activated by TNF-R1 in the light of these findings are discussed.
KeywordsRing Domain Ubiquitin Chain Death Domain Interaction Linear Ubiquitin Chain Kinase RIPK1
We would like to thank Hiroyasu Nakano for TRAF2/TRAF5 double knock-out MEFs, Robert Brink for TRAF2 conditional knock-out mice, Michelle Kelliher for RIPK1− / − mice, and James Vince and Lynn Wong for their work that contributed significantly to this chapter.
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