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

Author

Listed:
  • 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
    Broad Institute of MIT and Harvard)

  • 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)

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.

Suggested Citation

  • Emilio Boada-Romero & Inmaculada Serramito-Gómez & María P. Sacristán & David L. Boone & Ramnik J. Xavier & Felipe X. Pimentel-Muiños, 2016. "The T300A Crohn’s disease risk polymorphism impairs function of the WD40 domain of ATG16L1," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11821
    DOI: 10.1038/ncomms11821
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