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

PLoS One. 2008;3(10):e3391. doi: 10.1371/journal.pone.0003391. Epub 2008 Oct 13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Autophagy / immunology
  • Autophagy-Related Proteins
  • Carrier Proteins / genetics*
  • Cells, Cultured
  • Crohn Disease / etiology
  • Crohn Disease / genetics*
  • Crohn Disease / immunology*
  • Epithelial Cells
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Mutation, Missense*
  • Salmonella / immunology*

Substances

  • ATG16L1 protein, human
  • Autophagy-Related Proteins
  • Carrier Proteins