Unconventional autophagy mediated by the WD40 domain of ATG16L1 is derailed by the T300A Crohn disease risk polymorphism

• Published in: Autophagy 2016-11, Vol.12 (11), p.2254-2255
• Main Authors: Serramito-Gómez, Inmaculada, Boada-Romero, Emilio, Pimentel-Muiños, Felipe X.
• Format: Article
• Language: English
• Subjects: ATG16L1; Autophagic Punctum; Autophagy - genetics; Autophagy-Related Proteins - chemistry; Autophagy-Related Proteins - genetics; Crohn disease; Crohn Disease - genetics; Genetic Predisposition to Disease; Humans; Mutation - genetics; Polymorphism, Single Nucleotide - genetics; risk allele T300A; Risk Factors; Staphylococcus aureus; TMEM59; unconventional autophagy; WD40 Repeats; xenophagy
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1216303

A coding polymorphism of the critical autophagic effector ATG16L1 (T300A) increases the risk of Crohn disease, but how this mutation influences the function of ATG16L1 has remained unclear. In a recent report, we showed that the A300 allele alters the ability of the C-terminal WD40 domain of ATG16L1 to interact with proteins containing a specific amino acid motif able to recognize this region. This defect impairs the capacity of the motif-containing transmembrane molecule TMEM59 to induce the unconventional autophagic labeling of the same single-membrane vesicles where this protein is located. Such alteration derails the intracellular trafficking of TMEM59 and the xenophagic response against bacterial infection. In contrast, canonical autophagy remains unaffected in the presence of ATG16L1 T300A . These data argue that the T300A polymorphism impairs the unconventional autophagic activities carried out by the WD40 domain, a region of ATG16L1 whose function has remained poorly understood.