Gene Set: CADWELL_ATG16L1_TARGETS_DN

Standard name CADWELL_ATG16L1_TARGETS_DN
Systematic name M12482
Brief description Genes down-regulated in Paneth cell (part of intestiinal epithelium) of mice with hypomorphic (reduced function) form of ATG16L1 [GeneID=55054].
Full description or abstract 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.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 18849966   Authors: Cadwell K,Liu JY,Brown SL,Miyoshi H,Loh J,Lennerz JK,Kishi C,Kc W,Carrero JA,Hunt S,Stone CD,Brunt EM,Xavier RJ,Sleckman BP,Li E,Mizushima N,Stappenbeck TS,Virgin HW 4th
Exact source Table 1S
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Organism Mus musculus
Contributed by Jessica Robertson (MSigDB Team)
Source platform AFFY_Mouse430
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Version history 3.0: First introduced

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