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 Brown; Cisca Wijmenga; Ramnik J Xavier

doi:10.1016/j.celrep.2015.05.045

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

Cell Rep. 2015 Jun 30;11(12):1905-18. doi: 10.1016/j.celrep.2015.05.045. Epub 2015 Jun 18.

Authors

Jakob Begun¹, Kara G Lassen², Humberto B Jijon³, Leigh A Baxt⁴, Gautam Goel⁴, Robert J Heath⁵, Aylwin Ng⁶, Jenny M Tam⁷, Szu-Yu Kuo⁸, Eduardo J Villablanca⁶, Lola Fagbami⁸, Marije Oosting⁹, Vinod Kumar¹⁰, Monica Schenone⁸, Steven A Carr⁸, Leo A B Joosten⁹, Jatin M Vyas⁷, Mark J Daly¹¹, Mihai G Netea⁹, Gordon D Brown¹², Cisca Wijmenga¹⁰, Ramnik J Xavier¹³

Affiliations

¹ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Mater Research Institute, University of Queensland, Brisbane, QLD 4101, Australia.
² Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: klassen@broadinstitute.org.
³ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁴ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁸ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
¹⁰ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
¹¹ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹² Aberdeen Fungal Group, Division of Applied Medicine, CLSM, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
¹³ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Autophagy / genetics
Autophagy-Related Proteins
Carrier Proteins / genetics*
Crohn Disease / genetics*
Crohn Disease / microbiology
Crohn Disease / pathology
Genetic Predisposition to Disease
Genomics
Humans
Lectins, C-Type / biosynthesis
Lectins, C-Type / genetics*
Mice
Receptors, Mitogen / biosynthesis
Receptors, Mitogen / genetics*
Risk Factors
Salmonella / pathogenicity
Salmonella Infections / genetics*
Salmonella Infections / microbiology

Substances

ATG16L1 protein, human
Autophagy-Related Proteins
CLEC12A protein, human
Carrier Proteins
Lectins, C-Type
Receptors, Mitogen

Associated data

GEO/GSE68765
GEO/GSE69132

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding