Phosphorylation of Lamin A/C regulates structural integrity of the nuclear envelope

Shuaiyu Liu; Fangyuan Xiong; Zhen Dou; Lingluo Chu; Yihan Yao; Ming Wang; Xuebiao Yao; Xing Liu; Zhikai Wang

doi:10.1016/j.jbc.2024.108033

Phosphorylation of Lamin A/C regulates structural integrity of the nuclear envelope

J Biol Chem. 2024 Nov 28:108033. doi: 10.1016/j.jbc.2024.108033. Online ahead of print.

Authors

Shuaiyu Liu¹, Fangyuan Xiong², Zhen Dou², Lingluo Chu³, Yihan Yao⁴, Ming Wang¹, Xuebiao Yao⁵, Xing Liu⁶, Zhikai Wang⁷

Affiliations

¹ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China.
² MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China.
³ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511400, China.
⁴ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Cambridge University Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
⁵ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China. Electronic address: yaoxb@ustc.edu.cn.
⁶ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China. Electronic address: xing1017@ustc.edu.cn.
⁷ MOE Key Laboratory for Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, University of Science and Technology of China, Hefei 230027, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230027, China. Electronic address: wangzk@ustc.edu.cn.

PMID: 39615679
DOI: 10.1016/j.jbc.2024.108033

Abstract

Dynamic disassembly and reconstruction of the nuclear lamina during entry and exit of mitosis, respectively, are pivotal steps in proliferation of higher eukaryotic cells. Although numerous post-translational modifications of lamin proteins have been identified, key factors driving the nuclear lamina dynamics remain elusive. Here we identified CDK1-elicited phosphorylation sites on endogenous Lamin A/C and characterized their functions in regulation of the nuclear lamina. Specifically, mass spectrometry revealed CDK1-mediated phosphorylation of Lamin A/C at the N-terminal Thr19/Ser22 and the C-terminal Ser390/Ser392 during mitosis. Importantly, the phospho-mimicking 4D mutant T19D/S22D/S390D/S392D completely disrupted Lamin A filamentous structure in interphase cells. Conversely, the non-phosphorylatable mutant T19A/S22A and especially the 4A mutant T19A/S22A/S390A/S392A protected Lamin A from depolymerization during mitosis. These results suggest that phosphorylation and dephosphorylation of both N- and C-terminal sites regulate the nuclear lamina dynamics. Engineering the non-phosphorylatable mutant T19A/S22A into the endogenous LMNA gene resulted in nuclear abnormalities and micronucleus formation during telophase. Perturbation of the Lamin A phosphorylation is shown to prevent proper nuclear envelope dynamics and impair nuclear integrity. These findings reveal a previously undefined link between the CDK1-elicited Lamin A phosphorylation dynamics, nuclear envelope plasticity, and genomic stability during the cell cycle.

Keywords: CDK1; Lamin A; mitosis; nuclear integrity; phosphorylation.