| First Author | Boada-Romero E | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 11821 | PubMed ID | 27273576 |
| Mgi Jnum | J:239896 | Mgi Id | MGI:5882000 |
| Doi | 10.1038/ncomms11821 | Citation | Boada-Romero E, et al. (2016) The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1. Nat Commun 7:11821 |
| abstractText | 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. |
