The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1
Sacristán, María P.
Boone, David L.
Pimentel-Muiños, Felipe X.
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CitationBoada-Romero, Emilio, Inmaculada Serramito-Gómez, María P. Sacristán, David L. Boone, Ramnik J. Xavier, and Felipe X. Pimentel-Muiños. 2016. “The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1.” Nature Communications 7 (1): 11821. doi:10.1038/ncomms11821. http://dx.doi.org/10.1038/ncomms11821.
AbstractA 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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