title: 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.
authors.affiliation: 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.
authors.forename: Jakob
authors.initials: J
authors.lastname: Begun
authors.affiliation: 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.
authors.forename: Kara G
authors.initials: KG
authors.lastname: Lassen
authors.affiliation: 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.
authors.forename: Humberto B
authors.initials: HB
authors.lastname: Jijon
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Baxt
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heath
authors.affiliation: 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.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Tam
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Kuo
authors.affiliation: 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.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Villablanca
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Lola
authors.initials: L
authors.lastname: Fagbami
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jatin M
authors.initials: JM
authors.lastname: Vyas
authors.affiliation: 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.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Aberdeen Fungal Group, Division of Applied Medicine, CLSM, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: 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.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D000483:Alleles; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D011975:Receptors, Mitogen / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors; D012475:Salmonella / Q000472:pathogenicity; D012480:Salmonella Infections / Q000235:genetics* / Q000382:microbiology
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; C485220:CLEC12A protein, human; D002352:Carrier Proteins; D037181:Lectins, C-Type; D011975:Receptors, Mitogen