Size-scaling promotes senescence-like changes in proteome and organelle content

Abstract Senescent cells typically have an enlarged cell size but the reason for this has not been fully elucidated. As abnormal cell size may alter protein concentrations and cellular functionality, we used proteomic data from 59 unperturbed human cell lines to systematically characterize cell-size dependent changes in intracellular protein concentrations and organelle content. Increase in cell size leads to ubiquitous transcriptionally and post-transcriptionally regulated reorganization and dilution of the proteome. Many known senescence proteins display disproportionate size-scaling consistent with their altered expression in senescent cells, while lysosomes and the endoplasmic reticulum expand in larger cells contributing to the senescence phenotype. Analysis of organelle proteome expression identifies p53 and retinoblastoma pathways as mediators of size-scaling, consistent with their role in senescence. Taken together, cell size can alter cellular fitness and function through cumulative reorganization of the proteome and organelle content. An extreme consequence of this pervasive size-scaling appears to be senescence.