Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2.
Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2.
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DOI：
10.1101/gad.318709.118
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发表时间：
2018-12-01
影响因子：
10.5
通讯作者：
Thorner J
中科院分区：
文献类型：
--
作者：
Leskoske KL;Roelants FM;Emmerstorfer-Augustin A;Augustin CM;Si EP;Hill JM;Thorner J
在这里，Leskoske等人研究了TORC 2活性如何响应细胞包膜状态的变化而调节。他们证明了TORC2亚基Avo2是Slt2的直接靶点，Slt2是细胞壁完整性途径的MAPK，他们的发现为TORC2功能和调控提供了新的见解。酿酒酵母雷帕霉素靶蛋白复合物2（Saccharomycescerevisiae target of rapamycin，TOR）是调节细胞膜脂质和蛋白质稳态的重要因子。TORC2活性如何响应细胞包膜状态的变化而调节尚不清楚。在这里，我们证明TORC 2亚基Avo 2是Slt2的直接靶点，Slt2是细胞壁完整性途径的促分裂原活化蛋白激酶（MAPK）。通过过度表达上游Slt2激活因子（Pkc1）的组成型活性等位基因或生长素诱导的负性Slt2调节因子（Sln1）的降解来激活Slt2，以Slt2依赖的方式在其MAPK磷酸化受体位点引起Avo2的过度磷酸化，并减少TORC 2介导的其主要下游效应因子蛋白激酶Ypk1的磷酸化。Avo2的缺失或拟磷酸化Avo2等位基因的表达使细胞对两种应激（多球菌素处理和升高的外源性乙酸）敏感，细胞需要TORC 2激活Ypk 1才能生存。因此，Avo2是最佳TORC 2活性所必需的，并且Slt2介导的Avo2磷酸化下调TORC 2信号传导。与野生型Avo2相比，磷酸化模拟Avo2显示出明显的质膜位移，表明Slt2通过促进Avo2解离来抑制TORC 2。我们的研究结果是第一次证明TORC2功能是由MAPK介导的磷酸化调节的。
Here, Leskoske et al. studied how TORC2 activity is modulated in response to changes in the status of the cell envelope. They demonstrate that TORC2 subunit Avo2 is a direct target of Slt2, the MAPK of the cell wall integrity pathway, and their findings provide new insights into TORC2 function and regulation. Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.
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