Abstract
SummaryRIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.
Highlights
The nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2 are cytosolic Nod-like receptor (NLR) family proteins that function in the innate immune system to detect pathogenic bacteria (Philpott et al, 2014)
RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases
We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective
Summary
The nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2 are cytosolic Nod-like receptor (NLR) family proteins that function in the innate immune system to detect pathogenic bacteria (Philpott et al, 2014). NOD activation induces pro-inflammatory signaling by receptor-interacting protein kinase 2 (RIPK2, known as RIP2 or RICK), which plays an obligatory and specific role in activation of NOD-dependent, but not Toll-like receptor responses (Park et al, 2007). Signaling by RIPK2 is dependent on an N-terminal kinase domain with dual Ser/Thr and Tyr kinase activities (Dorsch et al, 2006; Tigno-Aranjuez et al, 2010), as well as a C-terminal caspase activation and recruitment domain (CARD) that mediates CARD-CARD domain assembly with activated NODs (Inohara et al, 1999; Ogura et al, 2001b). RIPK2 induces an antibacterial autophagic response by signaling between NODs and the autophagy factor ATG16L1 (Cooney et al, 2010; Homer et al, 2012)
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