School of Life Sciences, University of Science and Technology of China, 230027, Hefei, Anhui, China.
CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
Nat Commun. 2018 Jul 6;9(1):2639. doi: 10.1038/s41467-018-05105-8.
The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota. Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized distribution of cell-junction proteins in intestinal epithelial cells. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model.
III 类 PI3-激酶（PI3KC3）是一种负责生成磷脂酰肌醇 3-磷酸（PI3P）的酶，PI3P 是囊泡膜的关键组成部分。在这里，我们报告斑马鱼中 PI3KC3 的缺失会导致肠道损伤和炎症。在 pik3c3 突变体中，肠道管形成但无法维持。基因表达分析显示，屏障功能相关的炎症性肠病（IBD）易感性基因（E-钙粘蛋白、HNF4A、TTC7A）受到抑制，而突变体中炎症反应基因受到刺激。组织学分析显示中性粒细胞浸润到突变体的肠道上皮细胞中，并清除肠道微生物群。然而，肠道微生物似乎是可有可无的，因为在无菌条件下培养的突变体具有相似的肠道缺陷。从机制上讲，我们表明 PI3KC3 缺乏会抑制 PI3P 的形成，并破坏肠道上皮细胞中细胞连接蛋白的极化分布。这些结果不仅揭示了 PI3KC3 在肠道稳态中的作用，还提供了一个斑马鱼 IBD 模型。
