Abstract
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.
Highlights
Cellular senescence is characterized by the arrest of cell proliferation, which can be induced by various intrinsic and extrinsic stress factors; according to these factors, cellular senescence can be categorized as replicative senescence (RS), which is caused by long-term cell division; oncogene-induced senescence (OIS); DNA damage-induced senescence (DDIS); and oxidative stress-induced senescence (OSIS)
We identified 725 and 483 differentially expressed proteins (DEPs) in the nucleus (336 upregulated and 389 downregulated in senescent cells) and the cytoplasm (270 upregulated and 213 downregulated), respectively, with each DEP associated with two or more unique DE peptides that showed consistent up- or downregulation (Fig. 1b, c; Supplementary Table 2)
We focused on the top 10 clusters: C1 and C6 included up- and downregulated genes shared among all the models, respectively (‘all shared cluster’); C2-3 and C7-8 included up- and downregulated genes predominantly common to the nuclear barrier-induced senescence (NBIS) and RS models, respectively (‘NBIS-RS clusters’); C4 and C9-10 included up- and downregulated genes predominantly evident in the stress-induced senescence models (‘stress clusters’); and C5 included upregulated genes that were upregulated in the RCC1 shRNA-transfected senescence and OIS models (‘RCC1-OIS cluster’)
Summary
Cellular senescence is characterized by the arrest of cell proliferation, which can be induced by various intrinsic and extrinsic stress factors; according to these factors, cellular senescence can be categorized as replicative senescence (RS), which is caused by long-term cell division; oncogene-induced senescence (OIS); DNA damage-induced senescence (DDIS); and oxidative stress-induced senescence (OSIS). All these types of senescence share common senescent hallmarks, such as permanent growth arrest, genomic instability, senescenceassociated β-galactosidase (SA-β-gal) expression, the senescenceassociated secretory phenotype, and heterochromatin foci formation[1] in addition to common transcriptomic signatures of cellular senescence[2]. Aged yeast cells show decreased transport across the nuclear membrane[18]
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