Journal
EMBO JOURNAL
Volume 27, Issue 2, Pages 373-383Publisher
WILEY
DOI: 10.1038/sj.emboj.7601962
Keywords
NLR; Nod1; Nod2; RICK; TAK1
Categories
Funding
- NIDDK NIH HHS [R01 DK067628] Funding Source: Medline
- NIGMS NIH HHS [R01 GM060421, R01 GM60421] Funding Source: Medline
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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-kappa B through RICK, a caspase-recruitment domain-containing kinase. However, the mechanism by which RICK activates NF-kappa 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 I kappa B 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-kappa B activation.
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