Conserved nucleocytoplasmic density homeostasis drives cellular organization across eukaryotes

Abstract

AbstractThe packing and confinement of macromolecules in the cytoplasm and nucleoplasm has profound implications for cellular biochemistry. How intracellular density distributions vary and affect cellular physiology remains largely unknown. Here, we show that the nucleus is less dense than the cytoplasm and that living systems establish and maintain a constant density ratio between these compartments. Using label-free biophotonics and theory, we show that nuclear density is set by a pressure balance across the nuclear envelopein vitro,in vivoand during early development. Nuclear transport establishes a specific nuclear proteome that exerts a colloid osmotic pressure, which, assisted by entropic chromatin pressure, draws water into the nucleus. UsingC. elegans, we show that while nuclear-to-cytoplasmic (N/C)volumeratios change during early development, the N/Cdensityratio is robustly maintained. We propose that the maintenance of a constant N/Cdensityratio is the biophysical driver of one of the oldest tenets of cell biology: the N/Cvolumeratio. In summary, this study reveals a previously unidentified homeostatic coupling of macromolecular densities that drives cellular organization with implications for pathophysiologies such as senescence and cancer.