Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes.
Bibliographical noteFunding Information:
The authors are grateful to Samsung Advanced Institute of Technology (SAIT) colleagues Y.S. Kim, M.S. Kim, B.G. Moon, and H.T. Kang for their assistance. We also thank S.-E. Lee, D.-E. Kim, and H.-Y. Cho for their assistance. This research was supported by SAIT, the DGIST R&D Program and the Institute for Basic Science (IBS-R013-A1) of the Ministry of Science, ICT and Technology (MSIT) of KOREA. This study was also supported by the Brain Research Program (NRF-2017M3C7A1027472), the Basic Research Program (NRF-2019R1C1C1006262, NRF-2020R1A2C2013416, NRF-2020M3A9D8038014, and NRF-2020R1A2C2009439), the Basic Research Laboratory program (NRF-2019R1A4A1024278) through the National Research Foundation (NRF) funded by the MSIT, KRIBB Research Initiative Program (KGM5422113), and Chonnam National University R&D Program Grant for Research Chair Professor.
© 2021, The Author(s).
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry