The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1.
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.
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.
Emilio
E
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, Salamanca 37007, Spain.
Inmaculada
I
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, Salamanca 37007, Spain.
María P
MP
Sacristán
Departments of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, Indiana 46617, USA.
David L
DL
Boone
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Ramnik J
RJ
Xavier
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.
Felipe X
FX
Pimentel-Muiños
D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D021381:Protein Transport; D012307:Risk Factors; D013211:Staphylococcus aureus / Q000502:physiology; D000071678:WD40 Repeats
C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C000606148:TMEM59 protein, human; D053148:Caspase 3