Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant

• Published in: PloS one 2008-10, Vol.3 (10), p.e3391-e3391
• Main Authors: Kuballa, Petric, Huett, Alan, Rioux, John D, Daly, Mark J, Xavier, Ramnik J
• Format: Article
• Language: English
• Subjects: Alanine; Amino acids; Autophagy; Autophagy - genetics; Autophagy - immunology; Autophagy-Related Proteins; Bacteria; Bacterial infections; Biology; Biosynthesis; Carrier Proteins - genetics; Cell death; Cells, Cultured; Cloning; Crohn Disease - etiology; Crohn Disease - genetics; Crohn Disease - immunology; Crohn's disease; Crohns disease; Deoxyribonucleic acid; DNA; Epithelial Cells; Gastroenterology and Hepatology/Inflammatory Bowel Disease; Gastrointestinal diseases; Genetic Predisposition to Disease; Genetics and Genomics/Genetics of Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Health risks; Human papillomavirus; Humans; Immunology/Innate Immunity; Infections; Inflammatory bowel diseases; Intestine; Medical research; Medical schools; Mutagenesis; Mutation, Missense; Pathogenesis; Phagocytosis; Phagosomes; Plasmids; Polyclonal antibodies; Population genetics; Proteins; Risk analysis; Risk factors; Salmonella; Salmonella - immunology; Threonine; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003391

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.