A unique role for autophagy and Atg16L1 in Paneth cells in murine and human intestine

By K. Cadwell, John Y. Liu, Sarah L. Brown, H. Miyoshi, Joy Loh, J. Lennerz, C. Kishi, Wumesh Kc, Javier A. Carrero, S. Hunt and 8 more. Nature, 2008

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Susceptibility to Crohn’s disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn’s disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn’s disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn’s disease patients carrying the Crohn’s disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn’s disease patients homozygous for the ATG16L1 Crohn’s disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn’s disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/458bdef2974e37e07d4e5d9b0ea2e192d74dde8e

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Citations in the corpus

Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome (2019, background): “ATG16L1 deficiency has been found in association with a decrease in Paneth cell function, while polymorphism in the ATG16L1 gene affected the immune pathways which are involved in executing autophagy and in the proper handling of intracellular bacteria [187].”
Pattern recognition receptors and inflammation. (2010, background): “Furthermore, ATG16L1 is critical for the normal function of intestinal Paneth cells (Cadwell et al., 2008).”
Current understanding of dysbiosis in disease in human and animal models (2016, background): “In both humans and mice homozygous for the risk allele, there were no morphology abnormalities in the ileum, but abnormalities in Paneth cell granule secretion were displayed.(75) With ATG16L1 depletion, Paneth cells had significantly decreased numbers of anti-”
Exercise–induced BCL2–regulated autophagy is required for muscle glucose homeostasis (2012, background): “To evaluate whether impaired exercise-induced AMPK activation in vivo is due to deficient autophagy, rather than potential autophagy-independent effects of the BCL2 AAA mutation or monoallelic loss of beclin 1, we examined exercise-induced AMPK activation in Atg16l1 HM mice that are hypomorphic”
Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis (2011, background): “Mouse strains with engineered hypomorphic expression of Atg16l1 resulted in abnormalities in Paneth cell granule exocytosis, as well as increased expression of leptin, adiponectin, a variety of acute-phase reactants, and genes associated with lipid metabolism and peroxisome proliferator-activate”
Autophagy, Immunity, and Microbial Adaptations (2009, background): “(3) Autophagy also affects homeostasis of T cells (Pua et al., 2009), B cells (Miller et al., 2008), and specialized granulocytes of the intestinal epithelium known as Paneth cells (Cadwell et al., 2008).”
The Inflammasome: A Caspase-1 Activation Platform Regulating Immune Responses and Disease Pathogenesis (2009, background): “Furthermore, Atg16L1 also regulates the function of Paneth cell”