美国宾夕法尼亚大学Ken Cadwell研究小组宣布他们探明了克罗恩病风险等位基因ATG16L1的杂合性促进独特的蛋白质相互作用并保护免受细菌感染。这一研究成果发表在2025年5月14日出版的国际学术期刊《免疫学》上。

研究小组证明了小鼠中类似物替代的杂合性（Atg16L1T316A），而不是纯合性，可以防止致命的肠沙门氏菌伤寒杆菌感染。一个Atg16L1T316A拷贝足以通过炎性体激活来增强细胞因子的产生，这是保护所必需的。相比之下，Atg16L1T316A的两个拷贝抑制了lc3相关吞噬（LAP）的自噬相关过程，增加了敏感性。来自人供体的巨噬细胞与ATG16L1T300A杂合，显示炎症小体激活升高，而纯合性受损，与小鼠相似。这些结果阐明了T300A替代如何影响ATG16L1功能，并表明它可能有利于杂合子携带者，为其在人群中的流行提供了解释。

据了解，与克罗恩病相关的ATG16L1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体。

附：英文原文

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

Author: Xiaomin Yao, Eugene Rudensky, Patricia K. Martin, Brittany M. Miller, Isabel Vargas, Erin E. Zwack, Keenan A. Lacey, Zhengxiang He, Glaucia C. Furtado, Sérgio A. Lira, Victor J. Torres, Bo Shopsin, Ken Cadwell

Issue&Volume: 2025-05-14

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.

DOI: 10.1016/j.immuni.2025.04.023

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00186-4