Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation

Yanan Zhang,Xin Sui,Junhui Ba,Maosheng Wang,Yuan Chen,Tao Wang,Jiancheng Wang,Weijun Huang,Ke Qin ,Yinong Huang,Qiping Lu ,Xin Liu,Yue Shi,Jianye Cai,Yuan Qiu,Huiyong Shen,Yi Wang,Ying Zhou,Yuanjun Guan,Andy Peng Xiang

doi:10.1038/s41467-018-05808-y

Abstract

Emerging evidence has revealed that Nestin not only serves as a biomarker for multipotent stem cells, but also regulates cell proliferation and invasion in various tumors. However, the mechanistic contributions of Nestin to cancer pathogenesis are still unknown. In the present study, previously thought to reside exclusively in the cytoplasm, Nestin can also be found in the nucleus and participate in protecting tumor cells against cellular senescence. Specifically, we reveal that Nestin has a nuclear localization signal (aa318–aa347) at the downstream of rod domain. We then find nuclear Nestin could interact with lamin A/C. Mechanistic investigations demonstrate that Nestin depletion results in the activation of cyclin-dependent kinase 5 (Cdk5), which causes the phosphorylation of lamin A/C (mainly at S392 site) and its subsequent translocation to the cytoplasm for degradation. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C.

Highlights

Emerging evidence has revealed that Nestin serves as a biomarker for multipotent stem cells, and regulates cell proliferation and invasion in various tumors
It will be interesting to clarify whether Nestin is a nucleocytoplasmic shuttling protein, how Nestin participates in the regulation of lamina stability and what is functional significance of nuclearlocalized Nestin? In the present study, using non-small-cell lung carcinoma (NSCLC) model cell lines, we investigate the nuclear localization and functional roles of Nestin and reveal Nestin can import into the nucleus through a classical nuclear localization signal (NLS)
To further image nuclear deformation, we used tumor cells genetically labeled with green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm[25,26,27]

Summary

Introduction

Emerging evidence has revealed that Nestin serves as a biomarker for multipotent stem cells, and regulates cell proliferation and invasion in various tumors. Previously thought to reside exclusively in the cytoplasm, Nestin can be found in the nucleus and participate in protecting tumor cells against cellular senescence. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C. Our study demonstrated that Nestin can regulate proliferation and invasion of gastrointestinal stromal tumor cells by recruiting dynamin-related protein[1] to alter mitochondrial dynamics[13], indicating Nestin may participate in processing signal transduction, motility, and cellular stress and play a role in regulating spatial localization of cell organelles. In the present study, using non-small-cell lung carcinoma (NSCLC) model cell lines, we investigate the nuclear localization and functional roles of Nestin and reveal Nestin can import into the nucleus through a classical nuclear localization signal (NLS). We further show that Nestin stabilizes lamin A/C for maintaining nuclear integrity and protecting tumor cells from senescence

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Conclusion