A20-binding Inhibitor of Nuclear Factor-κB (NF-κB)-2 (ABIN-2) Is an Activator of Inhibitor of NF-κB (IκB) Kinase α (IKKα)-mediated NF-κB Transcriptional Activity

NF-kappa B transcription factors are pivotal players in controlling inflammatory and immune responses, as well as cell proliferation and apoptosis. Aberrant regulation of NF-kappa B and the signaling pathways that regulate its activity have been involved in various pathologies, particularly cancers, as well as inflammatory and autoimmune diseases. NF-kappa B activation is tightly regulated by the I kappa B kinase (IKK) complex, which is composed of two catalytic subunits IKK alpha and IKK beta, and a regulatory subunit IKK gamma/NEMO. Although IKK alpha and IKK beta share structural similarities, IKK alpha has been shown to have distinct biological functions. However, the molecular mechanisms that modulate IKK alpha activity have not yet been fully elucidated. To understand better the regulation of IKK alpha activity, we purified IKK alpha-associated proteins and identified ABIN-2. Here, we demonstrate that IKK alpha and IKK beta Both interact with ABIN-2 and impair its constitutive degradation by the proteasome. Nonetheless, ABIN-2 enhances IKK alpha- but not IKK beta-mediated NF-kappa B activation by specifically inducing IKK alpha autophosphorylation and kinase activity. Furthermore, we found that ABIN-2 serine 146 is critical for the ABIN-2-dependent IKK alpha transcriptional up-regulation of specific NF-kappa B target genes. These results imply that ABIN-2 acts as a positive regulator of NF-kappa B-dependent transcription by activating IKK alpha.