Article
- The EMBO Journal (2008) 27, 373 - 383
- doi:10.1038/sj.emboj.7601962
Published online: 13 December 2007
Subject Categories:
A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-
B activation
Mizuho Hasegawa1, Yukari Fujimoto2, Peter C Lucas1, Hiroyasu Nakano3, Koichi Fukase2, Gabriel Núñez1,4 and Naohiro Inohara1,5
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
- Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
- Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Biochemistry 2nd, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuou, Yamanashi, Japan
Correspondence to:
Naohiro Inohara, Department of Pathology, Comprehensive Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., C574 MSRB2, Ann Arbor, MI 48109, USA. Tel.: +1 734 936 3317; Fax: +1 734 647 9654; E-mail: ino@umich.edu
Received 26 September 2007; Accepted 23 November 2007
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-
B through RICK, a caspase-recruitment domain-containing kinase. However, the mechanism by which RICK activates NF-B 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 IB 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-B activation.
Keywords:
- NLR,
- Nod1,
- Nod2,
- RICK,
- TAK1
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