Robust network structure of the Sln1-Ypd1-Ssk1 three-component phospho-relay prevents unintended activation of the HOG MAPK pathway in Saccharomyces cerevisiae.
Robust network structure of the Sln1-Ypd1-Ssk1 three-component phospho-relay prevents unintended activation of the HOG MAPK pathway in Saccharomyces cerevisiae.
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DOI：
10.1186/s12918-015-0158-y
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发表时间：
2015-03-25
影响因子：
--
通讯作者：
McClean MN
中科院分区：
文献类型：
--
作者：
Dexter JP;Xu P;Gunawardena J;McClean MN
酵母酿酒酵母依赖于高渗透压甘油（HOG）信号通路来响应外部渗透压的增加。HOG通路在渗透压升高的条件下被快速激活，并调节细胞内的转录和代谢变化。然而，在正常生长条件下，由组氨酸激酶Sln 1、转移蛋白Ypd 1和反应调节剂Ssk 1组成的三组分磷酸化中继通过Ssk 1的磷酸化抑制HOG途径活性。HOG通路的这种抑制对于正常渗透压下的细胞适应性是必需的。然而，抑制的程度和机制是强大的磷酸中继组件的浓度波动很少受到关注。我们确定了Sln 1-Ypd 1-Ssk 1磷酸化中继是稳健的，即使在其三种组分的水平发生显著变化后，它也能够维持对HOG通路的抑制。然后，我们开发了一个生化现实的数学模型的磷酸继电器，这表明，鲁棒性是由于缓冲的一个大的过剩池的Ypd 1。我们通过实验证实，Ypd 1库的耗尽导致HOG通路的不适当激活。我们确定了缓冲的中间组件过量作为一种新的机制，通过它的磷酸继电器可以实现鲁棒性。这种缓冲需要多个组件，因此不适用于双组件系统，这表明多组件继电器的一个重要优势。本文的在线版本（doi：10.1186/s12918-015-0158-y）包含补充材料，可供授权用户使用。
The yeast Saccharomyces cerevisiae relies on the high-osmolarity glycerol (HOG) signaling pathway to respond to increases in external osmolarity. The HOG pathway is rapidly activated under conditions of elevated osmolarity and regulates transcriptional and metabolic changes within the cell. Under normal growth conditions, however, a three-component phospho-relay consisting of the histidine kinase Sln1, the transfer protein Ypd1, and the response regulator Ssk1 represses HOG pathway activity by phosphorylation of Ssk1. This inhibition of the HOG pathway is essential for cellular fitness in normal osmolarity. Nevertheless, the extent to and mechanisms by which inhibition is robust to fluctuations in the concentrations of the phospho-relay components has received little attention. We established that the Sln1-Ypd1-Ssk1 phospho-relay is robust—it is able to maintain inhibition of the HOG pathway even after significant changes in the levels of its three components. We then developed a biochemically realistic mathematical model of the phospho-relay, which suggested that robustness is due to buffering by a large excess pool of Ypd1. We confirmed experimentally that depletion of the Ypd1 pool results in inappropriate activation of the HOG pathway. We identified buffering by an intermediate component in excess as a novel mechanism through which a phospho-relay can achieve robustness. This buffering requires multiple components and is therefore unavailable to two-component systems, suggesting one important advantage of multi-component relays. The online version of this article (doi:10.1186/s12918-015-0158-y) contains supplementary material, which is available to authorized users.
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