Ver Heul AM, Fowler A, Ramaswamy S, Piper RC

NOD1 and NOD2 (Nucleotide-binding oligomerization domain-containing proteins) are intracellular pattern-recognition receptors that activate NF-κB and autophagy. These pathways rely on the CAspase Recruitment Domains (CARD) within the NODs, which serve as a protein interaction platforms that coordinately regulates immune signaling. We show that NOD1 CARD binds ubiquitin, in addition to ...

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directly binding its downstream targets RIP2 kinase and ATG16L. 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 the ligand-stimulated activity of NOD1 with a mutant CARD lacking Ub-binding, but retaining ATG16L and RIP2 binding, is hyperactive. 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 elevated ligand-stimulated NOD2 signaling. These data suggest that Ub-binding provides a negative-feedback loop on NOD-dependent activation of the RIP2.

Date: Jan. 08, 2013

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