Distinct tissue-specific roles for the disease-associated autophagy genes ATG16L2 and ATG16L1

The clear role of autophagy in human inflammatory diseases such as Crohn's disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn's disease-associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases including Crohn's disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood.To better understand its role, we generate and analyze the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn's disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease. Examination of the role of autophagy-related disease-associated genes using novel knock-out mouse model自噬（autophagy）在克罗恩病（Crohn's disease）等人类炎症性疾病中的明确作用，最初通过全基因组关联研究（genome-wide association studies）得以揭示，后续多项机制研究对其进行了深入解析。其中，ATG16L1在基因敲除（knockout）、功能减退突变（hypomorph）模型以及模拟克罗恩病相关T300A多态性的疾病模型中均得到了广泛研究。值得注意的是，ATG16L1存在唯一同源基因ATG16L2，后者亦独立参与克罗恩病、系统性红斑狼疮（systemic lupus erythematosus）等多种疾病的发病进程。然而，目前学界对ATG16L2在经典自噬通路及其他细胞功能中的贡献仍知之甚少。为进一步阐明ATG16L2的生物学功能，据我们所知，本研究构建并分析了首个ATG16L2基因敲除小鼠模型。研究结果显示，ATG16L1与ATG16L2在髓系、淋巴系及上皮细胞谱系的自噬调控与细胞发育过程中发挥着截然不同的作用。上述任一细胞谱系的失调，均可能参与克罗恩病、系统性红斑狼疮这类复杂疾病的发生发展，这也凸显了探究细胞特异性效应的研究价值。本研究还发现了ATG16L2与上皮细胞来源ATG16L1之间的新型遗传互作关系。本文将结合上述基因如何对人类疾病产生差异化贡献这一视角，对本研究发现展开讨论。本研究通过新型基因敲除小鼠模型，对自噬相关疾病关联基因的功能进行了探究。