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. Overall design: Examination of the role of autophagy-related disease-associated genes using novel knock-out mouse model

细胞自噬（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）得以鉴定，随后在多项机制研究中得到深入解析。其中，自噬相关16样蛋白1（ATG16L1）在基因敲除、减效突变（hypomorph）模型以及模拟克罗恩病相关T300A多态性的模型中得到了广泛研究。值得注意的是，ATG16L1仅存在一个同源基因ATG16L2，后者独立参与克罗恩病与系统性红斑狼疮（systemic lupus erythematosus）等疾病的发生发展。然而，目前对于ATG16L2在经典自噬通路及其他细胞功能中的作用机制仍知之甚少。为深入阐明ATG16L2的生物学功能，我们构建并分析了据我们所知首个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中，对细胞自噬与细胞发育的调控作用存在显著差异。上述任一细胞谱系的调控异常，均可能参与克罗恩病、系统性红斑狼疮等复杂疾病的发生，这也凸显了研究细胞特异性效应的重要价值。本研究还发现了ATG16L2与上皮细胞来源的ATG16L1之间存在全新的遗传互作关系。我们将结合上述基因如何特异性参与人类疾病发生的机制，对本研究发现展开讨论。整体实验设计：利用新型基因敲除小鼠模型，探究自噬相关疾病关联基因的生物学功能