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

Jakob Begun, Kara G Lassen, Humberto B Jijon, Leigh A Baxt, Gautam Goel, Robert J Heath, Aylwin Ng, Jenny M Tam, Szu-Yu Kuo, Eduardo J Villablanca, Lola Fagbami, Marije Oosting, Vinod Kumar, Monica Schenone, Steven A Carr, Leo A B Joosten, Jatin M Vyas, Mark J Daly, Mihai G Netea, Gordon D BrownCisca Wijmenga, Ramnik J Xavier

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1905-1918
Number of pages14
JournalCell Reports
Issue number12
Early online date18 Jun 2015
Publication statusPublished - 30 Jun 2015

Bibliographical note

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. This is an open access article under the CC BY-NC-ND license (

We thank Mathieu Platteel (UMCG) for microarray experiments and Natalia Nedelsky for editorial assistance. R.J.X. was supported by the Leona M. and Harry B. Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, and grants AI109725 and DK097485 from the NIH. C.W. is supported by funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Advanced grant agreement 2012-322698). M.G.N was supported by an ERC Consolidator Grant (no. 310372). G.D.B. was supported by the Wellcome Trust. H.B.J. was supported by a clinical fellowship from Alberta Innovates-Health Solutions (AIHS), Alberta, Canada.


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