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. 2025 Jun 10;58(6):1456-1468.e5.
doi: 10.1016/j.immuni.2025.04.023. Epub 2025 May 14.

Heterozygosity for Crohn's disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection

Xiaomin Yao  1 , Eugene Rudensky  1 , Patricia K Martin  1 , Brittany M Miller  2 , Isabel Vargas  2 , Erin E Zwack  1 , Keenan A Lacey  1 , Zhengxiang He  3 , Glaucia C Furtado  3 , Sérgio A Lira  3 , Victor J Torres  4 , Bo Shopsin  5 , Ken Cadwell  6
Affiliations

Heterozygosity for Crohn's disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection

Xiaomin Yao et al. Immunity. .

Abstract

The T300A substitution in ATG16L1 associated with Crohn's disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here, we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300A displayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence within the human population.

Keywords: ATG16L1; Crohn’s disease; LC3-associated phagocytosis; Salmonella; autophagy; balancing selection; inflammasome.

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Conflict of interest statement

Declaration of interests K.C. has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech, and Abbvie; consulted for or received honoraria from Puretech Health, Genentech, and Abbvie; and is an inventor on US patent 10,722,600 and provisional patents 62/935,035 and 63/157,225.

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