Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease.
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Abstract | Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics. |
Year of Publication | 2017
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Journal | Proc Natl Acad Sci U S A
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Volume | 114
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Issue | 43
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Pages | 11392-11397
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Date Published | 2017 10 24
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ISSN | 1091-6490
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DOI | 10.1073/pnas.1705748114
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PubMed ID | 29073062
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PubMed Central ID | PMC5664502
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Grant list | R37 GM038627 / GM / NIGMS NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
R01 AI137325 / AI / NIAID NIH HHS / United States
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