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J Exp Med. 2017 Dec 4;214(12):3687-3705. doi: 10.1084/jem.20170558. Epub 2017 Oct 31.

Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium.

Author information

1
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY.
2
Department of Microbiology, New York University School of Medicine, New York, NY.
3
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
4
Microscopy Core, Office of Collaborative Science, New York University School of Medicine, New York, NY.
5
Histopathology Core, Office of Collaborative Science, New York University School of Medicine, New York, NY.
6
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA.
7
Departments of Pathology and Laboratory Medicine, New Jersey Medical School and Robert Wood Johnson Medical School, Rutgers University, Newark, NJ.
8
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
9
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY vandenbm@mskcc.org.
10
Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
11
Weil Medical College of Cornell University, New York, NY.
12
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY ken.cadwell@med.nyu.edu.

Abstract

A variant of the autophagy gene ATG16L1 is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.

PMID:
29089374
PMCID:
PMC5716041
DOI:
10.1084/jem.20170558
[Indexed for MEDLINE]
Free PMC Article

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