Journal of Biological Chemistry
Volume 286, Issue 37, 16 September 2011, Pages 32277-32288
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Signal Transduction
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*

https://doi.org/10.1074/jbc.M111.236448Get rights and content
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NF-κB transcription factors are pivotal players in controlling inflammatory and immune responses, as well as cell proliferation and apoptosis. Aberrant regulation of NF-κB and the signaling pathways that regulate its activity have been involved in various pathologies, particularly cancers, as well as inflammatory and autoimmune diseases. NF-κB activation is tightly regulated by the IκB kinase (IKK) complex, which is composed of two catalytic subunits IKKα and IKKβ, and a regulatory subunit IKKγ/NEMO. Although IKKα and IKKβ share structural similarities, IKKα has been shown to have distinct biological functions. However, the molecular mechanisms that modulate IKKα activity have not yet been fully elucidated. To understand better the regulation of IKKα activity, we purified IKKα-associated proteins and identified ABIN-2. Here, we demonstrate that IKKα and IKKβ both interact with ABIN-2 and impair its constitutive degradation by the proteasome. Nonetheless, ABIN-2 enhances IKKα- but not IKKβ-mediated NF-κB activation by specifically inducing IKKα autophosphorylation and kinase activity. Furthermore, we found that ABIN-2 serine 146 is critical for the ABIN-2-dependent IKKα transcriptional up-regulation of specific NF-κB target genes. These results imply that ABIN-2 acts as a positive regulator of NF-κB-dependent transcription by activating IKKα.

Adaptor Proteins
Gene Expression
NF-κB
NF-κB Transcription Factor
Protein Phosphorylation
ABIN-2
IKK
IKKα
Signal Transduction

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*

This work was supported by grants from the Agence Nationale pour la Recherche, Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole, Cancéropole Ile-de-France, Institut National du Cancer, and Université Paris Descartes (to V. B.), postdoctoral funding from the Agence Nationale de la Recherche (to L. L.), grants from the Ligue Nationale contre le Cancer (to S. B. and F. H.), and a doctoral fellowship from the Ministère de la Recherche et des Technologies (to F. C.).

1

Both authors contributed equally to this work.

2

Both authors contributed equally to this work.

3

Present address: Institute of Molecular Oncology, Biomedical Sciences Research Center “Alexander Flemming,” 34 Fleming St., Vari, Greece.