Phosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy.
Phosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy.
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Ras-cAMP-PKA(Tpk2) 通路磷酸化 Jhd2 调节组蛋白修饰和自噬
DOI：
10.1038/s41467-022-33423-5
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发表时间：
2022-09-27
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
细胞需要协调基因表达与其代谢状态，以维持细胞稳态和生长。细胞如何将营养物质的可利用性转化为适当的基因表达仍然知之甚少。在这里，我们表明，糖酵解调节组蛋白修饰和基因表达的激活蛋白激酶A（PKA）通过Ras环AMP途径。PKA的催化亚基Tpk 2通过响应葡萄糖可用性在Ser321和Ser340处磷酸化Jhd2来拮抗Jhd2催化的H3K4去甲基化。Tpk2催化的Jhd2磷酸化损害其核定位，减少其与染色质的结合，并促进其多聚泛素化和蛋白酶体降解。Tpk 2催化的Jhd2磷酸化也通过阻止组蛋白脱乙酰酶Rpd3与染色质的结合来维持H3K14乙酰化。通过磷酸化Jhd2，Tpk 2调节基因表达，维持正常的时间寿命并促进自噬。这些结果提供了代谢和组蛋白修饰之间的直接联系，并揭示了细胞如何重新连接其对营养信号的生物反应。细胞如何将营养物质的可利用性转化为适当的基因表达仍然知之甚少。在这里，作者表明，营养传感器，蛋白激酶A调节组蛋白修饰和基因转录磷酸化组蛋白去甲基化酶。
Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth. How cells transduce nutrient availability to appropriate gene expression remains poorly understood. Here we show that glycolysis regulates histone modifications and gene expression by activating protein kinase A (PKA) via the Ras-cyclic AMP pathway. The catalytic subunit of PKA, Tpk2 antagonizes Jhd2-catalyzed H3K4 demethylation by phosphorylating Jhd2 at Ser321 and Ser340 in response to glucose availability. Tpk2-catalyzed Jhd2 phosphorylation impairs its nuclear localization, reduces its binding to chromatin, and promotes its polyubiquitination and degradation by the proteasome. Tpk2-catalyzed Jhd2 phosphorylation also maintains H3K14 acetylation by preventing the binding of histone deacetylase Rpd3 to chromatin. By phosphorylating Jhd2, Tpk2 regulates gene expression, maintains normal chronological life span and promotes autophagy. These results provide a direct connection between metabolism and histone modifications and shed lights on how cells rewire their biological responses to nutrient signals. How cells transduce nutrient availability to appropriate gene expression remains poorly understood. Here the authors show that the nutrient sensor, protein kinase A modulates histone modifications and gene transcription by phosphorylating histone demethylase.
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