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The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1

AutorBoada-Romero, Emilio ; Serramito-Gómez, Inmaculada; Sacristán, María P. ; Boone, David L.; Xavier, Ramnik J.; Pimentel-Muiños, Felipe X.
Fecha de publicación2016
EditorNature Publishing Group
CitaciónNature Communications 7: 11821 (2016)
ResumenA 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.
Versión del editorhttps://doi.org/10.1038/ncomms11821
Identificadoresdoi: 10.1038/ncomms11821
e-issn: 2041-1723
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