GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-10-02 DOI:10.1126/science.ads8728

Changqian Zhou, Miao Zhang, Jason Murray, Joao Paulo, Steve Gygi, Sichen Shao, Malcolm Whitman, Tracy Keller

引用次数: 0

Abstract

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.

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GCN1将GCN2偶联至核糖体状态，启动氨基酸反应通路信号

在营养剥夺过程中，蛋白激酶GCN2的激活调节细胞存活和代谢稳态。除了氨基酸胁迫外，GCN2还可被多种细胞胁迫激活。GCN2的激活与未带电trna、特定核糖体蛋白和翻译阻滞条件有关，但它们对激活的相对贡献尚不清楚。在这里，我们使用体外翻译来重建氨基酸胁迫下GCN2的激活，并比较了不同翻译应激源诱导的碰撞核糖体群体。GCN2信号的启动需要二核糖体传感器GCN1， GCN1以碰撞依赖的方式将GCN2招募到核糖体中，其中GCN2通过关键的核糖体相互作用被激活，并稳定地与碰撞核糖体相关联。我们的发现定义了GCN2活化的分子需求和动力学。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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