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.
Kuballa
Petric
P
Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Huett
Alan
A
Rioux
John D
JD
Daly
Mark J
MJ
Xavier
Ramnik J
RJ
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