A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease.
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.
Cadwell
Ken
K
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Patel
Khushbu K
KK
Komatsu
Masaaki
M
Virgin
Herbert W
HW
Stappenbeck
Thaddeus S
TS
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007421:Intestine, Small / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D019879:Paneth Cells / Q000378:metabolism* / Q000473:pathology
C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D000071193:Autophagy-Related Protein 7