A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease

Ken Cadwell, Khushbu K. Patel, Masaaki Komatsu, Herbert W. Virgin IV, Thaddeus S. Stappenbeck

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

Recently identified genetic determinants for enhanced susceptibility to Crohn disease (CD) included polymorphisms in the ATG16L1 and IRGM1 loci suggesting that the autophagy pathway plays a role in the pathogenesis of this disease. We have generated and analyzed three mouse models with diminished expression of autophagy proteins and show how the loss of function of various autophagy components contributes to CD pathogenesis. In the mouse small intestine, one common cellular target of Atg16L1, Atg5 and Atg7 is the Paneth cell, a specialized epithelial cell whose main function is the delivery of antimicrobial factors into the intestinal lumen by production and secretion of its characteristic cytoplasmic granules. Autophagy-deficient Paneth cells exhibited a striking loss of function in this granule exocytosis pathway. Transcriptional analysis revealed a gain of function whereby the gene expression associated with inflammatory responses was increased in autophagy-deficient Paneth cells. Importantly, we validated these findings by analyzing intestinal tissues from CD patients. Similar Paneth cell abnormalities were observed in CD patients homozygous for the ATG16L1 risk allele. Thus, one role for the autophagy pathway in CD pathogenesis is through selective effects on the biology and specialized properties of Paneth cells.

Original languageEnglish (US)
Pages (from-to)250-252
Number of pages3
JournalAutophagy
Volume5
Issue number2
DOIs
StatePublished - Feb 16 2009

Keywords

  • ATG16L1
  • ATG5
  • ATG7
  • Adipocytokine
  • Crohn disease
  • Exocytosis
  • Inflammatory bowel disease
  • Intestine
  • PPAR
  • Paneth cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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