A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation

Mizuho Hasegawa, Yukari Fujimoto, Peter C. Lucas, Hiroyasu Nakano, Koichi Fukase, Gabriel Núñez, Naohiro Inohara

Research output: Contribution to journalArticle

325 Citations (Scopus)

Abstract

Nod1 and Nod2 are intracellular proteins that are involved in host recognition of specific bacterial molecules and are genetically associated with several inflammatory diseases. Nod1 and Nod2 stimulation activates NF-κB through RICK, a caspase-recruitment domain-containing kinase. However, the mechanism by which RICK activates NF-κB in response to Nod1 and Nod2 stimulation is unknown. Here we show that RICK is conjugated with lysine-63-linked polyubiquitin chains at lysine 209 (K209) located in its kinase domain upon Nod1 or Nod2 stimulation and by induced oligomerization of RICK. Polyubiquitination of RICK at K209 was essential for RICK-mediated IKK activation and cytokine/chemokine secretion. However, RICK polyubiquitination did not require the kinase activity of RICK or alter the interaction of RICK with NEMO, a regulatory subunit of IκB kinase (IKK). Instead, polyubiquitination of RICK was found to mediate the recruitment of TAK1, a kinase that was found to be essential for Nod1-induced signaling. Thus, RICK polyubiquitination links TAK1 to IKK complexes, a critical step in Nod1/Nod2-mediated NF-κB activation.

Original languageEnglish
Pages (from-to)373-383
Number of pages11
JournalEMBO Journal
Volume27
Issue number2
DOIs
Publication statusPublished - 2008 Jan 23
Externally publishedYes

Keywords

  • NLR
  • Nod1
  • Nod2
  • RICK
  • TAK1

ASJC Scopus subject areas

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

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    Hasegawa, M., Fujimoto, Y., Lucas, P. C., Nakano, H., Fukase, K., Núñez, G., & Inohara, N. (2008). A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. EMBO Journal, 27(2), 373-383. https://doi.org/10.1038/sj.emboj.7601962