Immunity. 2009 Jun 19;30(6):789-801. Epub 2009 May 21.

Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2.External

Bertrand, M. J., Doiron, K., Labbe, K., Korneluk, R. G., Barker, P. A., Saleh, M.,
--- - Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Cellular inhibitor of apoptosis proteins (cIAPs) block apoptosis, but their physiological functions are still under investigation. Here, we report that cIAP1 and cIAP2 are E3 ubiquitin ligases that are required for receptor-interacting protein 2 (RIP2) ubiquitination and for nucleotide-binding and oligomerization (NOD) signaling. Macrophages derived from Birc2(-/-) or Birc3(-/-) mice, or colonocytes depleted of cIAP1 or cIAP2 by RNAi, were defective in NOD signaling and displayed sharp attenuation of cytokine and chemokine production. This blunted response was observed in vivo when Birc2(-/-) and Birc3(-/-) mice were challenged with NOD agonists. Defects in NOD2 signaling are associated with Crohn's disease, and muramyl dipeptide (MDP) activation of NOD2 signaling protects mice from experimental colitis. Here, we show that administration of MDP protected wild-type but not Ripk2(-/-) or Birc3(-/-) mice from colitis, confirming the role of the cIAPs in NOD2 signaling in vivo. This discovery provides therapeutic opportunities in the treatment of NOD-dependent immunologic and inflammatory diseases.
PMID: 19464198External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
CARD CIAP1 Link RIPK2 GST fusion protein pull-down Not specified Not specified E.coli Not specified Full length In vitro translation 19464198
CARD CIAP2 Link RIPK2 GST fusion protein pull-down Not specified Not specified E.coli Not specified Full length In vitro translation 19464198
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD CIAP1 Link RIPK2 Co-immunoprecipitation HEK293 Not specified Full length Not specified Full length 19464198
CARD CIAP2 Link RIPK2 Co-immunoprecipitation HEK293 Not specified Full length Not specified Full length 19464198
CARD NOD2 Link RIPK2 Co-immunoprecipitation HEK293 Not specified Not specified Not specified Full length 19464198
(Link: click this icon to show interactions only between the two corresponding DDs)