期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11821
关键词
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资金
- Ministerio de Ciencia e Innovacion of the Spanish Government [SAF2011-23714]
- Ministerio de Economia y Competitividad of the Spanish Government [SAF2014-53320-R]
- Broad Medical Research Program at Crohn's and Colitis Foundation of America (CCFA) [IBD-0369]
- Junta de Castilla y Leon local government (Department of Education) [CSI001A10-2, FIC016U14]
- Junta de Castilla y Leon local government (Department of Health) [SAN11-FXP]
- Fundacion Solorzano [FS/1-2009, FS/18-2014]
- NIH [R01DK097485, P30DK043351, U19AI109725]
- Helmsley Trust
- FEDER programme of the European Union
- FPU programme (Ministerio de Educacion, MEC, Spanish Government)
- Fundacion Moraza
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.
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