Integrated Genomics of Crohn’s Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy

Abstract

The polymorphism ATG16L1 T300A, associated with increased risk of Crohn's disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1(∗)300A risk allele. Clec12a(-/-) mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease.

DOI: 10.1016/j.celrep.2015.05.045

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@inproceedings{Begun2015IntegratedGO, title={Integrated Genomics of Crohn’s Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy}, author={Jakob Begun and Kara G. Lassen and Humberto B. Jijon and Leigh A. Baxt and Gautam Goel and R. V. Heath and A. C. Y. Ng and Jenny M. Tam and Szu-Yu Kuo and Eduardo J. Villablanca and Lola Fagbami and Marije Oosting and Vinod Kumar and Monica Schenone and Steven A. Carr and Leo A.B. Joosten and Jatin M. Vyas and Mark J. Daly and Mihai G. Netea and Gordon D. A. Brown and Cisca Wijmenga and Ramnik J. Xavier}, booktitle={Cell reports}, year={2015} }