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Impaired function of the WD40 domain of ATG16L1 caused by the T300A Crohn’s disease risk polymorphism

AutorSerramito-Gómez, Inmaculada; Pimentel-Muiños, Felipe X.
Fecha de publicación2016
EditorSociedad Española de Bioquímica y Biología Molecular
CitaciónXXXIX Congreso de la SEBBM (2016)
ResumenA coding allele of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn’s disease, but the underlying molecular defects introduced by this mutation are not fully understood. We show that T300A alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. This 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 ability to engage ATG16L1 in response to bacterial infection. Notably, these defects are independent of ATG16L1 T300A caspase cleavage. In addition, TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase 3 cleavage of the 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.
DescripciónResumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.
URIhttp://hdl.handle.net/10261/169544
Aparece en las colecciones: (IBMCC) Comunicaciones congresos
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