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

  • Nat Commun. 2016 Jun 8;7:11821. doi: 10.1038/ncomms11821.
Emilio Boada-Romero  1 ,  Inmaculada Serramito-Gómez  1 ,  María P Sacristán  1 ,  David L Boone  2 ,  Ramnik J Xavier  3  4 ,  Felipe X Pimentel-Muiños  1
Affiliations
  • 1. Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Centro de Investigación del Cáncer, Campus Miguel de Unamuno, Universidad de Salamanca, Salamanca 37007, Spain.
  • 2. Departments of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, Indiana 46617, USA.
  • 3. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
  • 4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
PMID: 27273576 DOI: 10.1038/ncomms11821
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.