Figure 3

Canonical activation of NFκB by TNF receptor. Binding of TNFα to TNF receptor 1 (TNFR1) leads to recruitment of the adaptor protein TNF receptor superfamily member 1A associated via death domain (TRADD), the ubiquitin ligases TNF receptor-associated factors 2 and 5 (TRAF2 and TRAF5), the inhibitor of apoptosis proteins cellular inhibitors of apoptosis 1 and 2 (cIAP1 and cIAP2), and the protein kinase RIPK1. This complex is also known as complex 1. The components of complex 1 are K63-ubiquitinated by cIAP1. This ubiquitination stimulates the ubiquitination-dependent recruitment of the linear ubiquitin chain assemblage complex (LUBAC) and the complexes composed of the kinases TAK1-TAB2-TAB3 and IKKα -IKKβ-IKKγ . LUBAC stimulates the formation of poly-ubiquitin chains on IKKγ and other members of the complex, with stabilization of the complex as a consequence. Besides, ubiquitination is necessary for the recruitment, retention, and activation of IKKα-IKKβ-IKKγ by TAK1. Next, IKKβ phosphorylates IκB, which leads to ubiquitin-dependent proteasomal degradation of IκB and activation of NFκB. E2, estradiol; IκB, inhibitor of NFκB; IKK, inhibitor of NFκB kinases; P, phosphogroup; TAB, TAK1-binding protein 1; TAK, transforming growth factor-beta activated kinase-1; Ub, ubiquitin.