Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1829-E1838. doi: 10.1073/pnas.1713991115. Epub 2018 Feb 5.
Eukaryotes respond to amino acid starvation by enhancing the translation of mRNAs encoding b-ZIP family transcription factors ( in and in mammals), which launch transcriptional programs to counter this stress. This pathway involves phosphorylation of the eIF2 translation factor by Gcn2-protein kinases and is regulated by upstream ORFs (uORFs) in the / 5' leaders. Here, we present evidence that the transcription factors that mediate this response are not evolutionarily conserved. Although cells of the fission yeast respond transcriptionally to amino acid starvation, they lack clear Gcn4 and Atf4 orthologs. We used ribosome profiling to identify mediators of this response in , looking for transcription factors that behave like We discovered a transcription factor (Fil1) translationally induced by amino acid starvation in a 5' leader and Gcn2-dependent manner. Like Gcn4, Fil1 is required for the transcriptional response to amino acid starvation, and Gcn4 and Fil1 regulate similar genes. Despite their similarities in regulation, function, and targets, Fil1 and Gcn4 belong to different transcription factor families (GATA and b-ZIP, respectively). Thus, the same functions are performed by nonorthologous proteins under similar regulation. These results highlight the plasticity of transcriptional networks, which maintain conserved principles with nonconserved regulators.
真核生物通过增强编码 b-ZIP 家族转录因子的 mRNA 的翻译来应对氨基酸饥饿（在 和 中），这些转录因子启动转录程序来应对这种应激。这条途径涉及 Gcn2-蛋白激酶对 eIF2 翻译因子的磷酸化，并且受到 /5' 先导区中的上游开放阅读框（uORFs）的调控。在这里，我们提供的证据表明，介导这种反应的转录因子在进化上没有保守性。尽管裂殖酵母 的细胞在转录水平上对氨基酸饥饿有反应，但它们缺乏明显的 Gcn4 和 Atf4 同源物。我们使用核糖体谱分析在 中鉴定了这种反应的介质，寻找行为类似于 的转录因子。我们发现了一种在 5' 先导区中由氨基酸饥饿诱导的转录因子（Fil1），并且这种诱导依赖于 Gcn2。与 Gcn4 一样，Fil1 是对氨基酸饥饿的转录反应所必需的，并且 Gcn4 和 Fil1 调节相似的基因。尽管它们在调控、功能和靶标上具有相似性，但 Fil1 和 Gcn4 属于不同的转录因子家族（分别为 GATA 和 b-ZIP）。因此，在相似的调控下，相同的功能由非同源蛋白执行。这些结果突出了转录网络的灵活性，这些网络以非保守的调控因子保持保守的原则。
