Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Mol Biol Cell. 2020 May 15;31(11):1183-1199. doi: 10.1091/mbc.E20-02-0161. Epub 2020 Mar 18.
The complex functions of cellular membranes, and thus overall cell physiology, depend on the distribution of crucial lipid species. Sac1 is an essential, conserved, ER-localized phosphatase whose substrate, phosphatidylinositol 4-phosphate (PI4P), coordinates secretory trafficking and plasma membrane function. PI4P from multiple pools is delivered to Sac1 by oxysterol-binding protein and related proteins in exchange for other lipids and sterols, which places Sac1 at the intersection of multiple lipid distribution pathways. However, much remains unknown about the roles of Sac1 in subcellular homeostasis and organismal development. Using a temperature-sensitive allele (), we show that Sac1 is required for structural integrity of the retinal floor. The β-integrin Myospheroid, which is necessary for basal cell adhesion, is mislocalized in retinas. In addition, the adhesion proteins Roughest and Kirre, which coordinate apical retinal cell patterning at an earlier stage, accumulate within retinal cells due to impaired endo-lysosomal degradation. Moreover, Sac1 is required for ER homeostasis in retinal cells. Together, our data illustrate the importance of Sac1 in regulating multiple aspects of cellular homeostasis during tissue development.
细胞膜的复杂功能，以及整体细胞生理学，取决于关键脂质种类的分布。Sac1 是一种必需的、保守的内质网定位磷酸酶，其底物磷脂酰肌醇 4-磷酸（PI4P）协调分泌运输和质膜功能。多种来源的 PI4P 通过氧化固醇结合蛋白和相关蛋白被递送到 Sac1，以换取其他脂质和甾醇，这使 Sac1 处于多种脂质分布途径的交汇处。然而，Sac1 在细胞内稳态和生物体发育中的作用仍知之甚少。我们使用一种温度敏感等位基因（）表明，Sac1 是视网膜地板结构完整性所必需的。β-整合素 Myospheroid 对于基底细胞粘附是必需的，在视网膜中发生了定位错误。此外，在早期协调视网膜细胞顶端模式形成的粘附蛋白 Roughest 和 Kirre 由于内体溶酶体降解受损而在视网膜细胞内积累。此外，Sac1 对视网膜细胞中的内质网稳态也是必需的。总之，我们的数据说明了 Sac1 在调节组织发育过程中细胞内稳态的多个方面的重要性。
