A20-binding inhibitor of nuclear factor-kappaB (NF-kappaB)-2 (ABIN-2) is an activator of inhibitor of NF-kappaB (IkappaB) kinase alpha (IKKalpha)-mediated NF-kappaB transcriptional activity

Laurent Leotoing, Fanny Chereau, Silvère Baron, Florent Hube, Hugo J Valencia, Didier Bordereaux, Jeroen A Demmers, John Strouboulis, Véronique Baud

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)32277-88
Number of pages12
JournalThe Journal of biological chemistry
Volume286
Issue number37
DOIs
Publication statusPublished - 16 Sept 2011

Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Animals
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase/genetics
  • Intracellular Signaling Peptides and Proteins/genetics
  • Mice
  • NF-kappa B/genetics
  • Phosphorylation/physiology
  • Proteasome Endopeptidase Complex/genetics
  • Transcription, Genetic/physiology
  • Up-Regulation/physiology

Fingerprint

Dive into the research topics of 'A20-binding inhibitor of nuclear factor-kappaB (NF-kappaB)-2 (ABIN-2) is an activator of inhibitor of NF-kappaB (IkappaB) kinase alpha (IKKalpha)-mediated NF-kappaB transcriptional activity'. Together they form a unique fingerprint.

Cite this