The Biotechnology Centre of Oslo, University of Oslo, Gaustadalléen 21, Oslo 0349, Norway.
Department of Biochemistry, University of Cambridge, Building O, Downing Site, Cambridge CB2 1QW, UK.
Curr Biol. 2017 Jan 23;27(2):175-188. doi: 10.1016/j.cub.2016.11.037. Epub 2016 Dec 29.
Extracellular cues regulate cell fate, and this is mainly achieved through the engagement of specific transcriptional programs. The TORC1 and TORC2 complexes mediate the integration of nutritional cues to cellular behavior, but their interplay is poorly understood. Here, we use fission yeast to investigate how phosphatase activity participates in this interplay during the switch from proliferation to sexual differentiation. We find that loss of PP2A-B55 enhances the expression of differentiation-specific genes and leads to premature conjugation. pab1 deletion brings about a transcriptional profile similar to TORC1 inactivation, and deletion of pab1 overcomes the repression of differentiation genes in cells overexpressing TORC1. Importantly, we show that this effect is mediated by an increased TORC2-AKT (Gad8) signaling. Under nutrient-rich conditions, PP2A-B55 dephosphorylates Gad8 Ser546, repressing its activity. Conversely, TORC1 inactivation upon starvation leads to the inactivation of PP2A-B55 through the Greatwall-Endosulfin pathway. This results in the activation of Gad8 and the commitment to differentiation. Thus, PP2A-B55 enables a crosstalk between the two TOR complexes that controls cell-fate decisions in response to nutrient availability.
细胞外线索调节细胞命运，这主要是通过特定转录程序的参与来实现的。TORC1 和 TORC2 复合物介导营养线索与细胞行为的整合，但它们之间的相互作用知之甚少。在这里，我们使用裂殖酵母来研究在从增殖到有性分化的转变过程中，磷酸酶活性如何参与这种相互作用。我们发现，PP2A-B55 的缺失增强了分化特异性基因的表达，并导致过早的接合。pab1 缺失带来类似于 TORC1 失活的转录谱，并且在过表达 TORC1 的细胞中，缺失 pab1 可以克服分化基因的抑制。重要的是，我们表明这种效应是通过增加的 TORC2-AKT (Gad8) 信号传导介导的。在营养丰富的条件下，PP2A-B55 去磷酸化 Gad8 Ser546，抑制其活性。相反，饥饿时 TORC1 的失活通过 Greatwall-Endosulfin 途径导致 PP2A-B55 的失活。这导致 Gad8 的激活和分化的启动。因此，PP2A-B55 使两种 TOR 复合物之间能够进行交流，从而根据营养可用性控制细胞命运决定。
