The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27273576.
- Also identified by DOI 10.1038/ncomms11821 and PMC identifier 4899871.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
Medical subject headings
- Autophagy-Related Proteins
- Carrier Proteins
- Crohn Disease
- Genetic Predisposition to Disease
- Polymorphism, Single Nucleotide
- WD40 Repeats