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A two-pore channel protein required for regulating mTORC1 activity on starvation.
BMC Biology ( IF 4.4 ) Pub Date : 2020-01-22 , DOI: 10.1186/s12915-019-0735-4
Fu-Sheng Chang 1 , Yuntao Wang 1 , Phillip Dmitriev 1 , Julian Gross 2 , Antony Galione 2 , Catherine Pears 1
Affiliation  

BACKGROUND Two-pore channels (TPCs) release Ca2+ from acidic intracellular stores and are implicated in a number of diseases, but their role in development is unclear. The social amoeba Dictyostelium discoideum proliferates as single cells that aggregate to form a multicellular organism on starvation. Starvation is sensed by the mTORC1 complex which, like TPC proteins, is found on acidic vesicles. Here, we address the role of TPCs in development and under starvation. RESULTS We report that disruption of the gene encoding the single Dictyostelium TPC protein, TPC2, leads to a delay in early development and prolonged growth in culture with delayed expression of early developmental genes, although a rapid starvation-induced increase in autophagy is still apparent. Ca2+ signals induced by extracellular cAMP are delayed in developing tpc2- cells, and aggregation shows increased sensitivity to weak bases, consistent with reduced acidity of the vesicles. In mammalian cells, the mTORC1 protein kinase has been proposed to suppress TPC channel opening. Here, we show a reciprocal effect as tpc2- cells show an increased level of phosphorylation of an mTORC1 substrate, 4E-BP1. mTORC1 inhibition reverses the prolonged growth and increases the efficiency of aggregation of tpc2- cells. CONCLUSION TPC2 is required for efficient growth development transition in Dictyostelium and acts through modulation of mTORC1 activity revealing a novel mode of regulation.

中文翻译:

一种在饥饿时调节 mTORC1 活性所需的双孔通道蛋白。

背景双孔通道 (TPC) 从酸性细胞内储存释放 Ca2+ 并与许多疾病有关,但它们在发育中的作用尚不清楚。社会变形虫盘基网柄菌作为单细胞增殖,在饥饿时聚集形成多细胞生物。饥饿由 mTORC1 复合物感知,与 TPC 蛋白一样,它存在于酸性囊泡上。在这里,我们解决了 TPC 在开发和饥饿中的作用。结果 我们报告称,尽管饥饿诱导的自噬快速增加仍然明显,但编码单个网基网柄菌 TPC 蛋白 TPC2 的基因的破坏导致早期发育延迟和培养物生长延长,早期发育基因的表达延迟。由细胞外 cAMP 诱导的 Ca2+ 信号在发育中的 tpc2- 细胞中延迟,和聚集显示对弱碱的敏感性增加,与囊泡的酸度降低一致。在哺乳动物细胞中,mTORC1 蛋白激酶被提议抑制 TPC 通道的开放。在这里,我们展示了一种相互影响,因为 tpc2- 细胞显示出 mTORC1 底物 4E-BP1 的磷酸化水平增加。mTORC1 抑制逆转延长的生长并增加 tpc2- 细胞的聚集效率。结论 TPC2 是网基网柄菌高效生长发育转变所必需的,它通过调节 mTORC1 活性发挥作用,揭示了一种新的调节模式。我们显示了一种相互影响,因为 tpc2- 细胞显示 mTORC1 底物 4E-BP1 的磷酸化水平增加。mTORC1 抑制逆转延长的生长并增加 tpc2- 细胞的聚集效率。结论 TPC2 是网基网柄菌高效生长发育转变所必需的,它通过调节 mTORC1 活性发挥作用,揭示了一种新的调节模式。我们显示了一种相互影响,因为 tpc2- 细胞显示 mTORC1 底物 4E-BP1 的磷酸化水平增加。mTORC1 抑制逆转延长的生长并增加 tpc2- 细胞的聚集效率。结论 TPC2 是网基网柄菌高效生长发育转变所必需的,它通过调节 mTORC1 活性发挥作用,揭示了一种新的调节模式。
更新日期:2020-04-22
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