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PMID: 29089374 Published · ppublish English Journal Article

Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium.

The Journal of experimental medicine ·Vol. 214 ·No. 12 ·2017-12-04 ·Pages 3687-3705

Matsuzawa-Ishimoto Y, Shono Y, Gomez LE, Hubbard-Lucey VM, Cammer M, Neil J, Dewan MZ, Lieberman SR, Lazrak A, Marinis JM, Beal A, Harris PA, Bertin J, Liu C, Ding Y, van den Brink MRM, Cadwell K

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.

MeSH Terms
Animals Apoptosis Autophagy Autophagy-Related Proteins Caliciviridae Infections/pathology,virology Carrier Proteins/metabolism Cell Survival Cytoprotection Epithelial Cells/metabolism,pathology Gene Deletion Graft vs Host Disease/pathology,therapy Hematopoietic Stem Cell Transplantation Homeostasis Intestinal Mucosa/metabolism,pathology Mice Mice, Inbred C57BL Mitochondria/metabolism,ultrastructure Mutation/genetics Necrosis Norovirus/physiology Organoids/pathology Paneth Cells/metabolism,pathology Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism Tumor Necrosis Factor-alpha/metabolism
Chemicals
Atg16l1 protein, mouse Autophagy-Related Proteins Carrier Proteins Tumor Necrosis Factor-alpha Receptor-Interacting Protein Serine-Threonine Kinases Ripk1 protein, mouse
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Matsuzawa-Ishimoto Yu
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY. | Department of Microbiology, New York University School of Medicine, New York, NY.
Shono Yusuke ORCID
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
Gomez Luis E
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY.
Hubbard-Lucey Vanessa M
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY.
Cammer Michael ORCID
Microscopy Core, Office of Collaborative Science, New York University School of Medicine, New York, NY.
Neil Jessica
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY. | Department of Microbiology, New York University School of Medicine, New York, NY.
Dewan M Zahidunnabi
Histopathology Core, Office of Collaborative Science, New York University School of Medicine, New York, NY.
Lieberman Sophia R ORCID
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
Lazrak Amina
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
Marinis Jill M
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA.
Beal Allison ORCID
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA.
Harris Philip A ORCID
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA.
Bertin John
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA.
Liu Chen
Departments of Pathology and Laboratory Medicine, New Jersey Medical School and Robert Wood Johnson Medical School, Rutgers University, Newark, NJ.
Ding Yi
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
van den Brink Marcel R M ORCID
Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY vandenbm@mskcc.org. | Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. | Weil Medical College of Cornell University, New York, NY.
Cadwell Ken ORCID
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY ken.cadwell@med.nyu.edu. | Department of Microbiology, New York University School of Medicine, New York, NY.
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20170558
Email
vandenbm@mskcc.org
ken.cadwell@med.nyu.edu
Published
2017-12-04
Epub
2017-00-31
Pages
3687-3705
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC5716041
Subset
IM
Grants
NIAID NIH HHS · R01 AI101406 · United States
NCI NIH HHS · P30 CA016087 · United States
NHLBI NIH HHS · R01 HL069929 · United States
NIDDK NIH HHS · R01 DK093668 · United States
NIAID NIH HHS · R01 AI080455 · United States
NCI NIH HHS · P30 CA008748 · United States
NIAID NIH HHS · R01 AI121244 · United States
NIAID NIH HHS · R01 AI100288 · United States
NCRR NIH HHS · S10 RR023704 · United States
NIDDK NIH HHS · R01 DK103788 · United States
NHLBI NIH HHS · R01 HL123340 · United States
External Links
PubMed source DOI: 10.1084/jem.20170558 PMC Full Text View journal details
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