ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism

A coding allele of ATG16L1 that increases the risk of Crohn disease (T300A; rs2241880) impairs the interaction between the C-terminal WD40 domain (WDD) and proteins containing a WDD-binding motif, thus specifically inhibiting the unconventional autophagic activities of ATG16L1. In a recent publication we described a novel atypical role of ATG16L1 in the regulation of IL10R (interleukin 10 receptor) trafficking and signaling, an activity that involves direct interaction between the WDD and a target motif present in IL10RB (interleukin 10 receptor subunit beta). Here we show that, unexpectedly, neither the ability of ATG16L1 to interact with IL10RB nor its role in supporting IL10 signaling are altered by the T300A mutation. These results indicate that the ATG16L1T300A allele selectively impairs the interaction between the WDD and a subset of WDD-binding motif versions, suggesting that only a fraction of the unconventional activities mediated by ATG16L1 are required to prevent Crohn disease.
This work was supported by the Ministerio de Economía, Industria y Competitividad, Gobierno de España [SAF2017-88390-R, PID2020-114699RB-100]; Consejería de Educación, Junta de Castilla y León [SA042P17] and [CLC-2017-01]; Crohn’s and Colitis Foundation of America [IBD-0369]; Fundación Solórzano (USAL) [FS/18-2014]”