Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs.
Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs.
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DOI：
10.1128/mbio.02229-17
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发表时间：
2018-03-27
期刊：
影响因子：
6.4
通讯作者：
Brown AJP
中科院分区：
文献类型：
--
作者：
Herrero-de-Dios C;Day AM;Tillmann AT;Kastora SL;Stead D;Salgado PS;Quinn J;Brown AJP
在所有的真核生物界中，丝裂原活化蛋白激酶（MAPK）在细胞对环境信号的反应中起着关键作用。这些MAPK响应于特定输入通过高度保守的苏氨酸和酪氨酸残基的磷酸化而被激活，导致它们在细胞核中积累并激活其下游靶标。一个特定的MAP激酶可以调节不同的下游目标，这取决于输入信号的性质，从而提出了一个关键问题：什么定义的压力特异性输出的MAP激酶？我们发现，Hog1 MAPK有助于抗亚硝化应激白念珠菌，即使它显示最小的应力诱导的磷酸化在这些条件下。我们发现，Hog1成为氧化响应亚硝化应激，积累在细胞核中，并调节亚硝化应激诱导的转录组。特异性半胱氨酸残基的突变揭示了C156和C161共同起作用以促进胁迫抗性、Hog1介导的亚硝化胁迫诱导的基因表达、对吞噬细胞杀伤的抗性和白色念珠菌毒力。我们建议，Hog1的氧化，而不是其磷酸化，有助于亚硝化应激特异性反应的MAP激酶。丝裂原活化蛋白激酶在真核细胞对细胞外信号的应答中起关键作用，并且对于环境胁迫抗性至关重要。广泛接受的范例是MAP激酶通过磷酸化激活，然后触发其核积累和促进细胞适应的靶蛋白和基因的激活。我们的数据表明，其他形式的翻译后修饰可以调节白念珠菌中MAP激酶的功能。我们证明，Hog1是不显着磷酸化，在响应亚硝化胁迫，但它显示核积累，并有助于全球转录响应这种压力，以及促进亚硝化胁迫抗性。相反，亚硝化应激触发Hog1氧化还原状态的变化。我们还表明，特定的Hog1半胱氨酸残基影响其激活的压力基因。因此，替代翻译后修饰似乎调节MAP激酶的应激特异性输出。
In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulation in the nucleus and the activation of their downstream targets. A specific MAP kinase can regulate different downstream targets depending on the nature of the input signal, thereby raising a key question: what defines the stress-specific outputs of MAP kinases? We find that the Hog1 MAPK contributes to nitrosative-stress resistance in Candida albicans even though it displays minimal stress-induced phosphorylation under these conditions. We show that Hog1 becomes oxidized in response to nitrosative stress, accumulates in the nucleus, and regulates the nitrosative stress-induced transcriptome. Mutation of specific cysteine residues revealed that C156 and C161 function together to promote stress resistance, Hog1-mediated nitrosative-stress-induced gene expression, resistance to phagocytic killing, and C. albicans virulence. We propose that the oxidation of Hog1, rather than its phosphorylation, contributes to the nitrosative-stress-specific responses of this MAP kinase. Mitogen-activated protein kinases play key roles in the responses of eukaryotic cells to extracellular signals and are critical for environmental-stress resistance. The widely accepted paradigm is that MAP kinases are activated by phosphorylation, which then triggers their nuclear accumulation and the activation of target proteins and genes that promote cellular adaptation. Our data suggest that alternative forms of posttranslational modification can modulate MAP kinase functionality in Candida albicans. We demonstrate that Hog1 is not significantly phosphorylated in response to nitrosative stress, yet it displays nuclear accumulation and contributes to the global transcriptional response to this stress, as well as promoting nitrosative-stress resistance. Instead, nitrosative stress triggers changes in the redox status of Hog1. We also show that specific Hog1 cysteine residues influence its activation of stress genes. Therefore, alternative posttranslational modifications appear to regulate the stress-specific outputs of MAP kinases.