Skip to main content
. Author manuscript; available in PMC: 2014 Aug 1.
Published in final edited form as: Cell Signal. 2013 Apr 21;25(8):10.1016/j.cellsig.2013.04.005. doi: 10.1016/j.cellsig.2013.04.005

Fig. 1.

Fig. 1

TNFα-mediated transient IKK activation pathways. (A) Signaling pathways to full IKK activation. Upon ligation, TNFR1 recruits TRADD, RIP1, TRAF2, and cIAP1/2. TRAF2 and cIAP1/2, in conjunction with UbcH5, catalyze RIP1 ubiquitination through linear (M1-pUb) and K63 linkages (K63-pUb), and also undergo autoubiquitination through K63-linkage. K63-pUb recruits the TAK1-TAB1-TAB2 complex, and M1-pUb recruits the IKKα-IKKβ-NEMO complex, leading to TAK1-mediated activation of the early phase of IKK. Thereafter, K63-pUb recruits the HOIL-1L–HOIP complex, which in turn recruits and catalyzes linear ubiquitination of NEMO, leading to more IKK recruitment and full activation of IKK. Such full IKK activation is required for the efficient expression of NF-κB target genes. (B) RIP1-independent pathway to delayed IKK activation. RIP1 protein is not detectable in embryonic hepatocytes. As a result, upon TNFR1 ligation, receptor-recruited TRAF2 and cIAP1/2 undergo increased autoubiquitination through K63 and K48 linkages. The K63-pUb chains then recruit the TAK1-TAB1-TAB2 and HOIP–HOIL-1 complexes, leading to activation of the delayed phase of IKK. Such delayed IKK activation is sufficient for induction of some NF-κB target genes (e.g., IκBα and IP-10).