Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation

Shuangshuang Sun, Zhe Xu, Liying He, Yihui Shen, Yuqing Yan, Xubing Lv, Xujing Zhu, Wei Li, Wei-Ya Tian, Yongjun Zheng, Sen Lin, Yadong Sun and Lei Li ()
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Shuangshuang Sun: ShanghaiTech University
Zhe Xu: ShanghaiTech University
Liying He: ShanghaiTech University
Yihui Shen: ShanghaiTech University
Yuqing Yan: HuaDong Hospital Affiliated to Fudan University
Xubing Lv: ShanghaiTech University
Xujing Zhu: ShanghaiTech University
Wei Li: ShanghaiTech University
Wei-Ya Tian: ShanghaiTech University
Yongjun Zheng: HuaDong Hospital Affiliated to Fudan University
Sen Lin: Army Medical University
Yadong Sun: ShanghaiTech University
Lei Li: ShanghaiTech University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Posttranslational modifications (PTMs) of tubulin, termed the “tubulin code”, play important roles in regulating microtubule functions within subcellular compartments for specialized cellular activities. While numerous tubulin PTMs have been identified, a comprehensive understanding of the complete repertoire is still underway. In this study, we report that α-tubulin lactylation is catalyzed by HDAC6 by using lactate to increase microtubule dynamics in neurons. We identify lactylation on lysine 40 of α-tubulin in the soluble tubulin dimers. Notably, lactylated α-tubulin enhances microtubule dynamics and facilitates neurite outgrowth and branching in cultured hippocampal neurons. Moreover, we discover an unexpected function of HDAC6, acting as the primary lactyltransferase to catalyze α-tubulin lactylation. HDAC6-catalyzed lactylation is a reversible process, dependent on lactate concentrations. Intracellular lactate concentration triggers HDAC6 to lactylate α-tubulin, a process dependent on its deacetylase activity. Additionally, the lactyltransferase activity may be conserved in HDAC family proteins. Our study reveals the primary role of HDAC6 in regulating α-tubulin lactylation, establishing a link between cell metabolism and cytoskeleton functions.

Date: 2024
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DOI: 10.1038/s41467-024-52729-0

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