Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium Journal Article

   


Authors: Matsuzawa-Ishimoto, Y.; Shono, Y.; Gomez, L. E.; Hubbard-Lucey, V. M.; Cammer, M.; Neil, J.; Dewan, M. Z.; Lieberman, S. R.; Lazrak, A.; Marinis, J. M.; Beal, A.; Harris, P. A.; Bertin, J.; Liu, C.; Ding, Y.; van den Brink, M. R. M.; Cadwell, K.
Article Title: Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium
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 TNFa-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 TNFa 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. © 2017 Matsuzawa-Ishimoto et al.
Keywords: controlled study; carrier protein; unclassified drug; gene deletion; genetics; mutation; nonhuman; mouse; animal; metabolism; animals; mice; cell death; cell survival; cell function; apoptosis; animal experiment; animal model; hematopoietic stem cell transplantation; caspase 3; pathology; necrosis; mice, inbred c57bl; physiology; c57bl mouse; virology; tumor necrosis factor-alpha; carrier proteins; graft versus host reaction; epithelium cell; epithelial cells; allogeneic hematopoietic stem cell transplantation; caspase 8; autophagy; homeostasis; graft vs host disease; mitochondria; cell protection; ultrastructure; mitochondrion; tumor necrosis factor; cytoprotection; intestine mucosa; norovirus; paneth cell; intestinal mucosa; paneth cells; inflammatory bowel disease; calicivirus infection; necroptosis; priority journal; article; antagonists and inhibitors; organoids; organoid; atg16l1 protein; autophagy related protein; atg16l1 protein, mouse; receptor interacting protein serine threonine kinase; ripk1 protein, mouse; small intestine epithelium; caliciviridae infections; receptor-interacting protein serine-threonine kinases
Journal Title: Journal of Experimental Medicine
Volume: 214
Issue: 12
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2017-12-04
Start Page: 3687
End Page: 3705
Language: English
DOI: 10.1084/jem.20170558
PUBMED: 29089374
PROVIDER: scopus
PMCID: PMC5716041
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85036529844&doi=10.1084%2fjem.20170558&partnerID=40&md5=5eccffc441ff1ba6b251683d033b7e05
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Marcel R M Van Den Brink
    616 Van Den Brink
  2. Yusuke Shono
    39 Shono
  3. Sophia Rose Lieberman
    14 Lieberman
  4. Amina Lazrak
    21 Lazrak
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