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Proc Natl Acad Sci U S A. 2014 May 27;111(21):7741-6. doi: 10.1073/pnas.1407001111. Epub 2014 May 12.

Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense.

Author information

  • 1Broad Institute, Cambridge, MA 02142;Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114;
  • 2Broad Institute, Cambridge, MA 02142;Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114;Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
  • 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
  • 4Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114;
  • 5Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114;Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
  • 6Broad Institute, Cambridge, MA 02142;
  • 7Broad Institute, Cambridge, MA 02142;Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
  • 8Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;Pathology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
  • 9Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • 10Pathology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
  • 11Broad Institute, Cambridge, MA 02142;Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114;
  • 12Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; and.
  • 13Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138 stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu.
  • 14Broad Institute, Cambridge, MA 02142;Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114;Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114; stuart_schreiber@harvard.edu xavier@molbio.mgh.harvard.edu.

Abstract

A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.

PMID:
24821797
[PubMed - indexed for MEDLINE]
PMCID:
PMC4040621
Free PMC Article
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