Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium Academic Article uri icon

Overview

MeSH Major

  • Graft vs Host Disease
  • Immunity, Innate
  • Lymphocytes
  • Thymus Gland

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.

publication date

  • December 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5716041

Digital Object Identifier (DOI)

  • 10.1084/jem.20170558

PubMed ID

  • 29089374

Additional Document Info

start page

  • 3687

end page

  • 3705

volume

  • 214

number

  • 12