Chemical genetic analysis of FTY720- and Ca2+ -sensitive mutants reveals a functional connection between FTY720 and membrane trafficking.,Genes to Cells

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Chemical genetic analysis of FTY720- and Ca2+ -sensitive mutants reveals a functional connection between FTY720 and membrane trafficking.
Genes to Cells ( IF 1.3 ) Pub Date : 2020-07-18 , DOI: 10.1111/gtc.12800
Kanako Hagihara _{1,

2} , Yuki Kanda ₁ , Kouki Ishida ₁ , Ryosuke Satoh ₁ , Teruaki Takasaki ₁ , Takuya Maeda ₂ , Reiko Sugiura ₁

Affiliation

FTY720, a sphingosine‐1‐phosphate (S1P) analog, is used as an immune modulator to treat multiple sclerosis. Accumulating evidence has suggested the mode of action of FTY720 independent of an S1P modulator. In fission yeast, FTY720 induces an increase in intracellular Ca²⁺ and ROS levels. We have previously identified 49 genes of which deletion causes FTY720 sensitivity. Here, we characterized the FTY720‐sensitive mutants in terms of their relevance to the Ca²⁺ homeostasis and identified the 16 FTY720‐ and Ca²⁺‐sensitive mutants (fcs mutants). Most of the FTY720‐sensitive mutants showed elevated Ca²⁺ levels and exhibited Ca²⁺ dysregulation by FTY720 treatment. One of the functional categories among the genes whose deletion renders cells susceptible to FTY720 and Ca²⁺ include the Golgi/endosomal membrane trafficking. Notably, FTY720, but not phosphorylated FTY720 incapable of inducing Ca²⁺ increase, inhibited the secretion of acid phosphatase in the wild‐type cells. Importantly, secretory defects of the Golgi/endosomal trafficking mutants, Vps45, or Ryh1 deletion, were further exacerbated by FTY720. Our fcs mutant screen also identified the adenylyl cyclase‐associated protein Cap1 and a Rictor homolog Ste20, whose deletion markedly exacerbated FTY720‐sensitive secretory impairment. Collectively, our data may suggest a synergistic impact of FTY720 combined with secretion perturbation on proliferation and Ca²⁺ homeostasis.

中文翻译：

FTY720和Ca2 +敏感突变体的化学遗传分析揭示了FTY720和膜运输之间的功能联系。

FTY720是一种鞘氨醇-1-磷酸（S1P）类似物，用作治疗多发性硬化症的免疫调节剂。越来越多的证据表明FTY720的作用方式独立于S1P调节剂。在裂变酵母中，FTY720诱导细胞内Ca ²⁺和ROS水平增加。我们以前已经鉴定出49个基因，这些基因的缺失引起FTY720敏感性。在这里，我们表征了FTY720敏感突变体在它们的相关性，以钙计²⁺稳态和识别的16 ˚F TY720-和Ç一个²⁺ -小号ensitive突变体（FCS突变体）。大多数对FTY720敏感的突变体均显示出升高的Ca ²⁺水平并显示出CaFTY720治疗导致²⁺失调。这些基因的缺失使细胞对FTY720和Ca ²⁺敏感的基因中的功能类别之一包括高尔基体/内膜膜运输。值得注意的是，FTY720可抑制野生型细胞中酸性磷酸酶的分泌，但不能磷酸化的FTY720不能诱导Ca ^2+的增加。重要的是，FTY720进一步加剧了高尔基体/内体运输突变体的分泌缺陷，Vps45或Ryh1缺失。我们的FCS突变体筛选还鉴定出了腺苷酸环化酶相关蛋白Cap1和Rictor同源Ste20，其缺失显着加剧了FTY720敏感的分泌障碍。总体而言，我们的数据可能表明FTY720结合分泌扰动对增殖和Ca ²⁺稳态具有协同作用。

更新日期：2020-09-14

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