The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that requires three conserved cysteine residues located adjacent to the catalytic loop. These residues were essential for Hog1-mediated protection against arsenic, were dispensable for the response to osmotic stress, and promoted the nuclear localization of Hog1 upon exposure of cells to arsenic. Hog1 promoted arsenic detoxification by stimulating phosphorylation of the transcription factor Yap8, promoting Yap8 nuclear localization, and stimulating the transcription of the only known Yap8 targets, ARR2 and ARR3, both of which encode proteins that promote arsenic efflux. The related human kinases ERK1 and ERK2 also bound to arsenic in vitro, suggesting that this may be a conserved feature of some members of the mitogen-activated protein kinase (MAPK) family. These data provide a mechanistic basis for understanding how stress-activated kinases can sense distinct threats and perform highly specific adaptive responses.

中文翻译：

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应力激活的蛋白激酶Hog1基于硫醇的直接威胁感测。

酵母应激激活的蛋白激酶Hog1以其在介导对渗透压的响应中的作用而闻名，但它也被各种机械上不同的环境应激物激活，包括热休克，内质网应激和砷。在渗透应激反应中，信号在上游被感知并通过激酶级联传递给Hog1。在这里，我们确定了Hog1功能的模式，其中Hog1通过直接的物理相互作用感应砷，需要直接与催化环相邻的三个保守的半胱氨酸残基。这些残基对于Hog1介导的抗砷保护是必不可少的，对于渗透压响应是必不可少的，并且在细胞暴露于砷后促进了Hog1的核定位。Hog1通过刺激转录因子Yap8的磷酸化，促进Yap8核定位并刺激唯一已知的Yap8靶标ARR2和ARR3的转录来促进砷的解毒作用，两者均编码促进砷外排的蛋白质。相关的人类激酶ERK1和ERK2在体外也与砷结合，表明这可能是促分裂原活化蛋白激酶（MAPK）家族某些成员的保守特征。这些数据为理解应力激活激酶如何感知不同的威胁并执行高度特异性的适应性反应提供了机械基础。相关的人类激酶ERK1和ERK2在体外也与砷结合，表明这可能是促分裂原活化蛋白激酶（MAPK）家族某些成员的保守特征。这些数据为理解应力激活激酶如何感知不同的威胁并执行高度特异性的适应性反应提供了机械基础。相关的人类激酶ERK1和ERK2在体外也与砷结合，表明这可能是促分裂原活化蛋白激酶（MAPK）家族某些成员的保守特征。这些数据为理解应力激活激酶如何感知不同的威胁并执行高度特异性的适应性反应提供了机械基础。