Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease

Proceedings of the National Academy of Sciences of the United States of America
Elizaveta S LeshchinerRamnik J Xavier

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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Citations

Nov 24, 2018·Nature Reviews. Immunology·Jürgen Ruland, Lara Hartjes
Nov 7, 2019·Journal of Cellular and Molecular Medicine·Ping LuoXiaoming Zhong
Feb 28, 2020·Nature·Daniel B Graham, Ramnik J Xavier
Aug 22, 2018·Frontiers in Immunology·Rebecca A DrummondMichail S Lionakis
May 28, 2019·Scientific Reports·Kun WangJiangyong Gu
May 30, 2019·Frontiers in Immunology·Angelo V MarzanoMassimo Cugno
Jan 24, 2020·Inflammatory Bowel Diseases·Guoqing Hou, Shrinivas Bishu
Jan 10, 2021·Mycoses·Alireza Beheshti-MaalMohammad Reza Zali
Feb 17, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Sjoukje-Marije HaismaCleo C van Diemen
Mar 19, 2021·Frontiers in Immunology·Mariano Prado AcostaBernd Lepenies
Apr 3, 2021·American Journal of Human Genetics·Minal CaliskanJoseph C Maranville
Jul 8, 2021·Biochemical Pharmacology·Suhadinie GamageAnjaneyulu Kowluru

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