The protein kinase Gcn2 and its effector protein Gcn1 are part of the general amino acid control signalling (GAAC) pathway best known in yeast for its function in maintaining amino acid homeostasis. Under amino acid limitation, Gcn2 becomes activated, subsequently increasing the levels of phosphorylated eIF2α (eIF2α-P). This leads to the increased translation of transcriptional regulators, such as Gcn4 in yeast and ATF4 in mammals, and subsequent re-programming of the cell's gene transcription profile, thereby allowing cells to cope with starvation. Xrn1 is involved in RNA decay, quality control and processing. We found that Xrn1 co-precipitates Gcn1 and Gcn2, suggesting that these three proteins are in the same complex. Growth under starvation conditions was dependent on Xrn1 but not on Xrn1-ribosome association, and this correlated with reduced eIF2α-P levels. Constitutively active Gcn2 leads to a growth defect due to eIF2α-hyperphosphorylation, and we found that this phenotype was independent of Xrn1, suggesting that xrn1 deletion does not enhance eIF2α de-phosphorylation. Our study provides evidence that Xrn1 is required for efficient Gcn2 activation, directly or indirectly. Thus, we have uncovered a potential new link between RNA metabolism and the GAAC.

中文翻译：

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有证据表明 Xrn1 与 Gcn1 形成复合物，并且是 eIF2α 完全磷酸化所必需的

蛋白激酶 Gcn2 及其效应蛋白 Gcn1 是一般氨基酸控制信号 (GAAC) 通路的一部分，在酵母中以其维持氨基酸稳态的功能而闻名。在氨基酸限制下，Gcn2 被激活，随后磷酸化 eIF2α (eIF2α-P) 的水平增加。这导致转录调节因子（例如酵母中的 Gcn4 和哺乳动物中的 ATF4）的翻译增加，以及随后细胞基因转录谱的重新编程，从而使细胞能够应对饥饿。 Xrn1 参与 RNA 降解、质量控制和加工。我们发现 Xrn1 共沉淀 Gcn1 和 Gcn2，表明这三种蛋白处于同一复合物中。饥饿条件下的生长依赖于 Xrn1，但不依赖于 Xrn1-核糖体关联，这与 eIF2α-P 水平降低相关。组成型活性 Gcn2 会因 eIF2α 过度磷酸化而导致生长缺陷，我们发现这种表型与 Xrn1 无关，表明 xrn1 缺失不会增强 eIF2α 去磷酸化。我们的研究提供了证据表明 Xrn1 是 Gcn2 直接或间接有效激活所必需的。因此，我们发现了 RNA 代谢和 GAAC 之间潜在的新联系。