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

Posttranslational modifications (PTMs) of tubulin, termed as 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 catalyzed by HDAC6 by using lactate to increase microtubule dynamics in neurons. We identified lactylation on lysine 40 of α-tubulin in the soluble tubulin dimers. Notably, lactylated α-tubulin enhanced microtubule dynamics and facilitated neurite outgrowth and branching in cultured hippocampal neurons. Moreover, we discovered a novel function of HDAC6, acting as the primary “writer” for α-tubulin lactylation. HDAC6-catalyzed lactylation was a reversible process, dependent on lactate concentrations. Intracellular lactate concentration triggered HDAC6 to lactylate α-tubulin, a process dependent on its deacetylase activity. Additionally, the catalytic activity for lactylation was 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.