Phosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy

Qi Yu, Xuanyunjing Gong, Yue Tong, Min Wang, Kai Duan, Xinyu Zhang, Feng Ge, Xilan Yu () and Shanshan Li ()
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Qi Yu: School of Life Sciences, Hubei University
Xuanyunjing Gong: School of Life Sciences, Hubei University
Yue Tong: School of Life Sciences, Hubei University
Min Wang: Chinese Academy of Sciences
Kai Duan: School of Life Sciences, Hubei University
Xinyu Zhang: School of Life Sciences, Hubei University
Feng Ge: Chinese Academy of Sciences
Xilan Yu: School of Life Sciences, Hubei University
Shanshan Li: School of Life Sciences, Hubei University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33423-5

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