HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity
| Autor: | Jingyan Li, Hanwei Yang, Min Huang, Wanqi Yang, Yanqi Mai, Guimei Guan, Tong Lin, Wenwei Luo, Meiting Chen, Lili Zhang, Chunmei Dai, Jing Lu, Peiqing Liu, Ruiming Liu, Ziqing Li, Zhuoming Li, Hong Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Aging Immunology Endogeny 030204 cardiovascular system & hematology Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Stress signalling 0302 clinical medicine Stress Physiological Human Umbilical Vein Endothelial Cells NLS Gene silencing Animals Aspartic Acid Endopeptidases Humans Gene Silencing Heme Vascular diseases Cellular Senescence Cell Nucleus Gene knockdown Nucleoplasm QH573-671 Chemistry Proto-Oncogene Proteins c-mdm2 Cell Biology Cell biology Up-Regulation Mice Inbred C57BL Molecular Docking Simulation Protein Transport 030104 developmental biology Gene Expression Regulation Gene Knockdown Techniques Mutation Tumor Suppressor Protein p53 Cytology Signal peptide peptidase Nucleophosmin Nuclear localization sequence Heme Oxygenase-1 Protein Binding |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 8, Pp 1-13 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases. |
| Databáze: | OpenAIRE |
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