α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation

• Published in: Nature communications Vol. 12; no. 1; pp. 4113 - 16
• Main Authors: Xie, Xuan, Wang, Shaogang, Li, Mingyi, Diao, Lei, Pan, Xingyu, Chen, Jijun, Zou, Weiguo, Zhang, Xu, Feng, Wenfeng, Bao, Lan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/19; 14/28; 14/34; 14/63; 631/378/2571; 631/80/128/1653; 82/80; 82/83; Acetylation; Antibodies; Axons; Brain research; Cell migration; Cerebral cortex; Cytokinesis; Cytoplasm; Embryos; Humanities and Social Sciences; Laboratories; Lysine; Methylation; Methyltransferase; Microtubules; Mimicry; Mitosis; Morphology; multidisciplinary; Neurons; Nucleation; Paclitaxel; Peptides; Polarization; Post-translation; Science; Science (multidisciplinary); Stem cells; Translation; Tubulin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24376-2

Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about α-TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation. α-TubK40me3 is enriched in mouse cerebral cortex during embryonic day (E)14 to E16. Knockdown of α-tubulin methyltransferase SETD2 at E14 leads to the defects in neuronal migration, which could be restored by overexpressing either a cytoplasm-localized SETD2 truncation or α-TubK40me3-mimicking mutant. Furthermore, α-TubK40me3 is preferably distributed on polymerized microtubules and potently promotes tubulin nucleation. Downregulation of α-TubK40me3 results in reduced microtubule abundance in neurites and disrupts neuronal polarization, which could be rescued by Taxol. Additionally, α-TubK40me3 is increased after losing α-tubulin K40 acetylation (α-TubK40ac) and largely rescues α-TubK40ac function. This study reveals a critical role of α-TubK40me3 in microtubule formation and neuronal development. Post-translational modifications of tubulins regulate microtubule properties and neural development. Here, the authors report that one such post-translational modification, α-TubK40me3, is required for neuronal polarization and migration by promoting microtubule formation.