Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis PMID: 34608293

ADC Targets in Oncology

2026-04-10

Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis

Nat Chem Biol. 2021 Dec;17(12):1314-1323. doi: 10.1038/s41589-021-00875-7.

Xiaoyu Song ^# ¹ ² , Fengrui Yang ^# ¹ ² , Xu Liu ^# ¹ ² , Peng Xia ^# ¹ , Wu Yin ¹ , Zhikai Wang ¹ ² , Yong Wang ³ , Xiao Yuan ¹ ⁴ , Zhen Dou ¹ , Kai Jiang ³ , Mingming Ma ¹ , Bing Hu ¹ , Rui Zhang ⁵ , Chao Xu ¹ , Zhiyong Zhang ¹ , Ke Ruan ¹ , Ruijun Tian ⁴ , Lin Li ⁶ , Tao Liu ⁷ , Donald L Hill ⁸ , Jianye Zang ⁹ , Xing Liu ¹⁰ ¹¹ , Jinsong Li ¹² , Jinke Cheng ¹³ , Xuebiao Yao ¹⁴ ¹⁵ ¹⁶

Affiliations

1. MOE Key Laboratory for Cellular Dynamics and Hefei National Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China.
2. Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA.
3. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
4. Department of Chemistry, Southern University of Science and Technology, Shenzhen, China.
5. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
6. Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
7. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
8. Comprehensive Cancer Center, University of Alabama, Birmingham, AL, USA.
9. MOE Key Laboratory for Cellular Dynamics and Hefei National Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China. [email protected].
10. MOE Key Laboratory for Cellular Dynamics and Hefei National Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China. [email protected].
11. Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA. [email protected].
12. Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. [email protected].
13. Department of Biochemistry, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
14. MOE Key Laboratory for Cellular Dynamics and Hefei National Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China. [email protected].
15. Keck Center for Organoids Plasticity, Morehouse School of Medicine, Atlanta, GA, USA. [email protected].
16. Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Spindle position control is essential for cell fate determination and organogenesis. Early studies indicate the essential role of the evolutionarily conserved Gαi/LGN/NuMA network in spindle positioning. However, the regulatory mechanisms that couple astral microtubules dynamics to the spindle orientation remain elusive. Here we delineated a new mitosis-specific crotonylation-regulated astral microtubule-EB1-NuMA interaction in Mitosis. EB1 is a substrate of TIP60, and TIP60-dependent crotonylation of EB1 tunes accurate spindle positioning in Mitosis. Mechanistically, TIP60 crotonylation of EB1 at Lys66 forms a dynamic link between accurate attachment of astral microtubules to the lateral cell cortex defined by NuMA-LGN and fine tune of spindle positioning. Real-time imaging of chromosome movements in HeLa cells expressing genetically encoded crotonylated EB1 revealed the importance of crotonylation dynamics for accurate control of spindle orientation during metaphase-anaphase transition. These findings delineate a general signaling cascade that integrates protein crotonylation with accurate spindle positioning for chromosome stability in Mitosis.