The paradox of proteasome granules.

Profound knowledge is available for the structure, function and regulation of proteasomes, the key proteases for ubiquitin-dependent protein degradation in dividing cells. Far less understood are proteasome structure and function in quiescence, the resting phase of our body's cells, as in yeast cells grown to stationary phase. In quiescent yeast proteasomes exit the nucleus and accumulate in cytoplasmic protein droplets, called proteasome storage granules (PSG). PSG-like structures also exist in non-dividing mammalian cells suggesting that the mechanism underlying PSG organization is conserved from yeast to human. The PSG has physiological significance as it protects yeast cells against stress and confers fitness during aging. The molecular architecture of PSG remains an enigma, since PSG freely move as spherical units without being surrounded by membranes through the cytoplasm. They rapidly resolve with the resumption of cell proliferation and proteasomes reenter the nucleus. Our systems biology and biochemical data revealed that PSG are mainly composed of proteasomes and free ubiquitin. Often intrinsically disordered proteins undergo liquid phase separations, allowing soluble proteins to condense into protein droplets in an aqueous solution. The question is which proteins and factors nucleate PSG formation, since proteasomes composed of folded subunits are able to degrade intrinsically disordered proteins.