Journal article
Ubiquitin Regulates Caspase Recruitment Domain-mediated Signaling by Nucleotide-binding Oligomerization Domain-containing Proteins NOD1 and NOD2
The Journal of biological chemistry, Vol.288(10), pp.6890-6902
03/08/2013
DOI: 10.1074/jbc.M112.413781
PMCID: PMC3591598
PMID: 23300079
Abstract
NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins) are intracellular pattern recognition receptors that activate inflammation and autophagy. These pathways rely on the caspase recruitment domains (CARDs) within the receptors, which serve as protein interaction platforms that coordinately regulate immune signaling. We show that NOD1 CARD binds ubiquitin (Ub), in addition to directly binding its downstream targets receptor-interacting protein kinase 2 (RIP2) and autophagy-related protein 16-1 (ATG16L1). NMR spectroscopy and structure-guided mutagenesis identified a small hydrophobic surface of NOD1 CARD that binds Ub. In vitro, Ub competes with RIP2 for association with NOD1 CARD. In vivo, we found that the ligand-stimulated activity of NOD1 with a mutant CARD lacking Ub binding but retaining ATG16L1 and RIP2 binding is increased relative to wild-type NOD1. Likewise, point mutations in the tandem NOD2 CARDs at positions analogous to the surface residues defining the Ub interface on NOD1 resulted in loss of Ub binding and increased ligand-stimulated NOD2 signaling. These data suggest that Ub binding provides a negative feedback loop upon NOD-dependent activation of RIP2.
Background: NOD1 and NOD2 are innate immune receptors implicated in inflammatory diseases.
Results: The CARDs of NOD1 and NOD2 bind ubiquitin; mutations that block this interaction increase inflammatory signaling.
Conclusion: NOD1 and NOD2 signaling is regulated in part by interaction of their CARDs with ubiquitin.
Significance: Understanding the regulatory mechanisms of NOD1 and NOD2 is crucial to defining their role in inflammation.
Details
- Title: Subtitle
- Ubiquitin Regulates Caspase Recruitment Domain-mediated Signaling by Nucleotide-binding Oligomerization Domain-containing Proteins NOD1 and NOD2
- Creators
- Aaron M. Ver Heul - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52246C. Andrew Fowler - Carver College of Medicine NMR Facility, Iowa City, Iowa 52246S. Ramaswamy - University of IowaRobert C. Piper - Institute of Molecular Biology and Biophysics
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(10), pp.6890-6902
- DOI
- 10.1074/jbc.M112.413781
- PMID
- 23300079
- PMCID
- PMC3591598
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 03/08/2013
- Academic Unit
- Molecular Physiology and Biophysics; Biochemistry and Molecular Biology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984297496602771
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