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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 ATG16L1 T300A  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. Abbreviations:  ATG, autophagy related; ATG16L1, autophagy related 16 like 1; BMDMs, bone marrow-derived macrophages; CRISPR, clustered regularly interspaced short palindromic repeats; CSF1/M-CSF, colony stimulating factor 1; FBS, fetal bovine serum; GSH, glutathione; IL10, interleukin 10; IL10R, interleukin 10 receptor; LPS, lipopolysaccharide; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; PMA, phorbol myristate acetate; p-STAT3: phosphorylated STAT3; qPCR, quantitative polymerase chain reaction; SDS, sodium dodecyl sulfate; sgRNA, single guide RNA; TMEM59, transmembrane protein 59; TNF, tumor necrosis factor; TNFAIP3/A20, TNF alpha induced protein 3; WDD, WD40 domain; WIPI2, WD repeat domain, phosphoinositide interacting 2

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