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

Mathieu J M Bertrand; Karine Doiron; Katherine Labbé; Robert G Korneluk; Philip A Barker; Maya Saleh

doi:10.1016/j.immuni.2009.04.011

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

Immunity. 2009 Jun 19;30(6):789-801. doi: 10.1016/j.immuni.2009.04.011. Epub 2009 May 21.

Authors

Mathieu J M Bertrand¹, Karine Doiron, Katherine Labbé, Robert G Korneluk, Philip A Barker, Maya Saleh

Affiliation

¹ Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

PMID: 19464198
DOI: 10.1016/j.immuni.2009.04.011

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
Animals
Apoptosis / immunology
Baculoviral IAP Repeat-Containing 3 Protein
Colitis / enzymology
Colitis / immunology
Colitis / pathology
Cytokines / immunology
Cytokines / metabolism
Immunity, Innate*
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / immunology
Inhibitor of Apoptosis Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Nod1 Signaling Adaptor Protein / agonists
Nod1 Signaling Adaptor Protein / immunology
Nod1 Signaling Adaptor Protein / metabolism*
Nod2 Signaling Adaptor Protein / agonists
Nod2 Signaling Adaptor Protein / immunology
Nod2 Signaling Adaptor Protein / metabolism*
Receptor-Interacting Protein Serine-Threonine Kinase 2
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / immunology
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
Receptors, Pattern Recognition / agonists
Receptors, Pattern Recognition / immunology
Receptors, Pattern Recognition / metabolism
Signal Transduction / drug effects
Signal Transduction / immunology
Ubiquitin-Protein Ligases
Ubiquitination / immunology

Substances

Cytokines
Inhibitor of Apoptosis Proteins
Nod1 Signaling Adaptor Protein
Nod2 Signaling Adaptor Protein
Receptors, Pattern Recognition
Acetylmuramyl-Alanyl-Isoglutamine
Baculoviral IAP Repeat-Containing 3 Protein
Birc2 protein, mouse
Birc3 protein, mouse
Ubiquitin-Protein Ligases
Receptor-Interacting Protein Serine-Threonine Kinase 2
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk2 protein, mouse