Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant.
The genetic risk factors predisposing individuals to the development of inflammatory bowel disease are beginning to be deciphered by genome-wide association studies. Surprisingly, these new data point towards a critical role of autophagy in the pathogenesis of Crohn's disease. A single common coding variant in the autophagy protein ATG16L1 predisposes individuals to the development of Crohn's disease: while ATG16L1 encoding threonine at amino acid position 300 (ATG16L1*300T) confers protection, ATG16L1 encoding for alanine instead of threonine (ATG16L1*300A, also known as T300A) mediates risk towards the development of Crohn's disease. Here we report that, in human epithelial cells, the Crohn's disease-associated ATG16L1 coding variant shows impairment in the capture of internalized Salmonella within autophagosomes. Thus, we propose that the association of ATG16L1*300A with increased risk of Crohn's disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.
Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Petric
P
Kuballa
Alan
A
Huett
John D
JD
Rioux
Mark J
MJ
Daly
Ramnik J
RJ
Xavier
D001343:Autophagy / Q000235:genetics* / Q000276:immunology; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D004847:Epithelial Cells; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020125:Mutation, Missense; D012475:Salmonella / Q000276:immunology*
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins