Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium

作者:Matsuzawa Ishimoto Yu; Shono Yusuke; Gomez Luis E; Hubbard Lucey Vanessa M; Cammer Michael; Neil Jessica; Dewan M Zahidunnabi; Lieberman Sophia R; Lazrak Amina; Marinis Jill M; Beal Allison; Harris Philip A; Bertin John; Liu Chen; Ding Yi; van den Brink Marcel R M*; Cadwell Ken*
来源:Journal of Experimental Medicine, 2017, 214(12): 3687-3705.
DOI:10.1084/jem.20170558

摘要

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 TNF alpha-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 TNF alpha 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.

  • 出版日期2017-12
  • 单位rutgers