Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease.
Proc Natl Acad Sci U S A
; 114(43): 11392-11397, 2017 10 24.
Article
em En
| MEDLINE
| ID: mdl-29073062
ABSTRACT
Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Variação Genética
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Ensaio de Imunoadsorção Enzimática
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Doenças Inflamatórias Intestinais
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Proteínas Adaptadoras de Sinalização CARD
Tipo de estudo:
Diagnostic_studies
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2017
Tipo de documento:
Article