Mechanisms of NF-κB inhibition by A20 in the TNFR1 signaling pathway. A20 is induced by NF-κB in the TNFR1 pathway and functions in a negative feedback loop. The A20 adaptor molecule TAX1BP1 is phosphorylated on Ser593 and Ser624 by IKKα which nucleates the A20 ubiquitin-editing complex and is essential for interactions between TAX1BP1, Itch, RNF11 and A20. The A20 ubiquitin-editing complex inhibits RIP1 K63-linked polyubiquitination to terminate NF-κB signaling downstream of TNFR1. IKK, IκB kinase; RNF11, ring finger protein 11; TAX1BP1, Tax1-binding protein 1; TNFR1, TNF receptor 1.