Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine
Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine
复制标题
DOI：
10.1073/pnas.1213212110
复制
发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
S. Takasuga;Y. Horie;J. Sasaki;G. Sun-Wada;N. Kawamura;Ryota Iizuka;K. Mizuno;S. Eguchi;Satoshi Kofuji;H. Kimura;Masakazu Yamazaki;Chihoko Horie;Eri Odanaga;Yoshiko Sato;S. Chida;K. Kontani;A. Harada;T. Katada;A. Suzuki;Y. Wada;H. Ohnishi;Takehiko Sasaki
中科院分区：
文献类型：
--
作者：
S. Takasuga;Y. Horie;J. Sasaki;G. Sun-Wada;N. Kawamura;Ryota Iizuka;K. Mizuno;S. Eguchi;Satoshi Kofuji;H. Kimura;Masakazu Yamazaki;Chihoko Horie;Eri Odanaga;Yoshiko Sato;S. Chida;K. Kontani;A. Harada;T. Katada;A. Suzuki;Y. Wada;H. Ohnishi;Takehiko Sasaki
膜磷酸肌醇的代谢对于多种细胞过程是至关重要的。磷脂酰肌醇-3，5-二磷酸[PtdIns（3，5）P2]控制酵母和哺乳动物细胞中细胞内膜运输系统的多个步骤。然而，除了在神经组织中，很少有人知道PtdIns（3，5）P2在哺乳动物中的生理功能。在这里，我们提供的遗传证据表明，III型磷脂酰肌醇磷酸激酶（PIPKIII），产生PtdIns（3，5）P2，是必不可少的极化上皮细胞的功能。PIPKIII基因缺失的小鼠胚胎在胚胎第8.5天死亡，这是因为内脏内胚层无法向外胚层提供母体营养。类似地，尽管出生了特异性PIPKIII缺陷小鼠，但它们无法茁壮成长，最终死于营养不良。在机制水平上，我们表明，PIPKIII调节蛋白质的运输到细胞的顶端膜结构域。重要的是，具有PIPKIII的精氨酸特异性缺失的小鼠表现出腹泻和血便，并且它们的肠道上皮层表现出炎症和纤维化，使我们的突变体成为炎性肠病的改进模型。总之，我们的数据表明，PIPKIII是两种不同类型的极化上皮细胞的结构和功能完整性所必需的，并表明PtdIns（3，5）P2代谢是肠上皮细胞膜运输和炎症性肠病发病机制之间的意外和关键联系。
The metabolism of membrane phosphoinositides is critical for a variety of cellular processes. Phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] controls multiple steps of the intracellular membrane trafficking system in both yeast and mammalian cells. However, other than in neuronal tissues, little is known about the physiological functions of PtdIns(3,5)P2 in mammals. Here, we provide genetic evidence that type III phosphatidylinositol phosphate kinase (PIPKIII), which produces PtdIns(3,5)P2, is essential for the functions of polarized epithelial cells. PIPKIII-null mouse embryos die by embryonic day 8.5 because of a failure of the visceral endoderm to supply the epiblast with maternal nutrients. Similarly, although intestine-specific PIPKIII-deficient mice are born, they fail to thrive and eventually die of malnutrition. At the mechanistic level, we show that PIPKIII regulates the trafficking of proteins to a cell’s apical membrane domain. Importantly, mice with intestine-specific deletion of PIPKIII exhibit diarrhea and bloody stool, and their gut epithelial layers show inflammation and fibrosis, making our mutants an improved model for inflammatory bowel diseases. In summary, our data demonstrate that PIPKIII is required for the structural and functional integrity of two different types of polarized epithelial cells and suggest that PtdIns(3,5)P2 metabolism is an unexpected and critical link between membrane trafficking in intestinal epithelial cells and the pathogenesis of inflammatory bowel disease.