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

Author

Listed:
  • 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
    Shanghai Clinical Research and Trial Center)

  • 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
    Shanghai Clinical Research and Trial Center)

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.

Suggested Citation

  • 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 & Lei Li, 2024. "Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52729-0
    DOI: 10.1038/s41467-024-52729-0
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