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

Emilio Boada-Romero, Inmaculada Serramito-Gómez, María P. Sacristán, David L. Boone, Ramnik J. Xavier and Felipe X. Pimentel-Muiños ()
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Emilio Boada-Romero: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Centro de Investigación del Cáncer, Campus Miguel de Unamuno, Universidad de Salamanca
Inmaculada Serramito-Gómez: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Centro de Investigación del Cáncer, Campus Miguel de Unamuno, Universidad de Salamanca
María P. Sacristán: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Centro de Investigación del Cáncer, Campus Miguel de Unamuno, Universidad de Salamanca
David L. Boone: Indiana University School of Medicine-South Bend
Ramnik J. Xavier: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Felipe X. Pimentel-Muiños: Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Centro de Investigación del Cáncer, Campus Miguel de Unamuno, Universidad de Salamanca

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11821

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