title: ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB.
abstract: Nuclear factor kappaB (NF-kappaB) plays a pivotal role in inflammation, immunity, stress responses, and protection from apoptosis. Canonical activation of NF-kappaB is dependent on the phosphorylation of the inhibitory subunit IkappaBalpha that is mediated by a multimeric, high molecular weight complex, called IkappaB kinase (IKK) complex. This is composed of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, NEMO/IKKgamma. The latter protein is essential for the activation of IKKs and NF-kappaB, but its mechanism of action is not well understood. Here we identified ABIN-1 (A20 binding inhibitor of NF-kappaB) as a NEMO/IKKgamma-interacting protein. ABIN-1 has been previously identified as an A20-binding protein and it has been proposed to mediate the NF-kappaB inhibiting effects of A20. We find that both ABIN-1 and A20 inhibit NF-kappaB at the level of the IKK complex and that A20 inhibits activation of NF-kappaB by de-ubiquitination of NEMO/IKKgamma. Importantly, small interfering RNA targeting ABIN-1 abrogates A20-dependent de-ubiquitination of NEMO/IKKgamma and RNA interference of A20 impairs the ability of ABIN-1 to inhibit NF-kappaB activation. Altogether our data indicate that ABIN-1 physically links A20 to NEMO/IKKgamma and facilitates A20-mediated de-ubiquitination of NEMO/IKKgamma, thus resulting in inhibition of NF-kappaB.
authors: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Federico II, University of Naples, via S. Pansini, 5, 80131 Naples, Italy.
authors: Claudio
authors: C
authors: Mauro
authors: Francesco
authors: F
authors: Pacifico
authors: Alfonso
authors: A
authors: Lavorgna
authors: Stefano
authors: S
authors: Mellone
authors: Alessio
authors: A
authors: Iannetti
authors: Renato
authors: R
authors: Acquaviva
authors: Silvestro
authors: S
authors: Formisano
authors: Pasquale
authors: P
authors: Vito
authors: Antonio
authors: A
authors: Leonardi