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Cell Rep DOI:10.1016/j.celrep.2015.05.045

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

Publication TypeJournal Article
Year of Publication2015
AuthorsBegun, J, Lassen, KG, Jijon, HB, Baxt, LA, Goel, G, Heath, RJ, Ng, A, Tam, JM, Kuo, S-Y, Villablanca, EJ, Fagbami, L, Oosting, M, Kumar, V, Schenone, M, Carr, SA, Joosten, LAB, Vyas, JM, Daly, MJ, Netea, MG, Brown, GD, Wijmenga, C, Xavier, RJ
JournalCell Rep
Volume11
Issue12
Pages1905-18
Date Published2015 Jun 30
ISSN2211-1247
KeywordsAlleles, Animals, Autophagy, Autophagy-Related Proteins, Carrier Proteins, Crohn Disease, Genetic Predisposition to Disease, Genomics, Humans, Lectins, C-Type, Mice, Receptors, Mitogen, Risk Factors, Salmonella, Salmonella Infections
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S2211-1247(15)00581-1
DOI10.1016/j.celrep.2015.05.045
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26095365?dopt=Abstract

Alternate JournalCell Rep
PubMed ID26095365
PubMed Central IDPMC4507440
Grant ListU19 AI109725 / AI / NIAID NIH HHS / United States
102705 / / Wellcome Trust / United Kingdom
P30 DK043351 / DK / NIDDK NIH HHS / United States
AI109725 / AI / NIAID NIH HHS / United States
322698 / / European Research Council / International
R01 AI097519 / AI / NIAID NIH HHS / United States
310372 / / European Research Council / International
DK097485 / DK / NIDDK NIH HHS / United States
084428 / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
R01 AI092084 / AI / NIAID NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States