Yao Xiaomin, Rudensky Eugene, Martin Patricia K, Miller Brittany M, Vargas Isabel, Zwack Erin E, Lacey Keenan A, He Zhengxiang, Furtado Glaucia C, Lira Sérgio A, Torres Victor J, Shopsin Bo, Cadwell Ken
Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Immunity. 2025 Jun 10;58(6):1456-1468.e5. doi: 10.1016/j.immuni.2025.04.023. Epub 2025 May 14.
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 (Atg16L1), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1 was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1 inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1 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.
与克罗恩病相关的ATG16L1基因中的T300A替换会损害自噬，然而高达50%的人类是该等位基因的杂合子。在此，我们证明小鼠（Atg16L1）中类似替换的杂合性而非纯合性可保护小鼠免受致死性鼠伤寒沙门氏菌感染。一份Atg16L1足以通过炎性小体激活增强细胞因子产生，这是保护所必需的。相反，两份Atg16L1会抑制与自噬相关的LC3相关吞噬作用（LAP）并增加易感性。来自ATG16L1基因杂合的人类供体的巨噬细胞表现出炎性小体激活增强，而纯合性则损害LAP，这与小鼠相似。这些结果阐明了T300A替换如何影响ATG16L1功能，并表明它对杂合携带者可能有益，为其在人群中的流行提供了解释。
