Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways

Prashant B. Shambharkar, Marzenna Blonska, Bhanu P. Pappu, Hongxiu Li, Yun You, Hiroaki Sakurai, Bryant G. Darnay, Hiromitsu Hara, Josef Penninger, Xin Lin

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

The IκB kinase (IKK) complex serves as the master regulator for the activation of NF-κB by various stimuli. It contains two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKα/β at its activation loop and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKKα/β activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKα/β phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKα/β and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.

Original languageEnglish (US)
Pages (from-to)1794-1805
Number of pages12
JournalEMBO Journal
Volume26
Issue number7
DOIs
StatePublished - Apr 4 2007

Keywords

  • IκB kinase
  • Phosphorylation
  • Ubiquitination

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Shambharkar, P. B., Blonska, M., Pappu, B. P., Li, H., You, Y., Sakurai, H., Darnay, B. G., Hara, H., Penninger, J., & Lin, X. (2007). Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways. EMBO Journal, 26(7), 1794-1805. https://doi.org/10.1038/sj.emboj.7601622