Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Abstract

Aging: Communication defects between nucleus and cytoplasm Disruption of signals passing into or out of nucleus may be involved in aging. As cells age, they become senescent, i.e., stop growing and dividing. Cellular senescence is charateristic of reduced responsiveness to various stresses. Recent studies have noted that communication between nucleus and cytoplasm is dysfunctional in senescent cells. But it has not been determined whether the defects in this communication brings to cellular aging. Sang Chul Park and co-workers at DGIST, KRIBB, CNU and SNU in South Korea investigated nuclear-cytoplasmic trafficking (NCT) in senescent cells and found that impairment of NCT caused cells to become senescent. As cells aged, transmission of signals into or out of nucleus was reduced. Studying cells in which NCT is deliberately blocked may illuminate how cells age. 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.