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Abstract

The ubiquitin-proteasome-system (UPS) fulfills an essential role in regulating protein homeostasis by spatially and temporally controlling proteolysis in an ATP- and ubiquitin-dependent manner. However, the localization of proteasomes is highly variable under diverse cellular conditions. In yeast, newly synthesized proteasomes are primarily localized to the nucleus during cell proliferation. Yeast proteasomes are transported into the nucleus through the nuclear pore either as immature subcomplexes or as mature enzymes via adaptor proteins Sts1 and Blm10, while in mammalian cells, post-mitotic uptake of proteasomes into the nucleus is mediated by AKIRIN2, an adaptor protein essentially required for nuclear protein degradation. Stressful growth conditions and the reversible halt of proliferation, i.e. quiescence, are associated with a decline in ATP and the re-organization of proteasome localization. Cellular stress leads to proteasome accumulation in membraneless granules either in the nucleus or in the cytoplasm. In quiescence, yeast proteasomes are sequestered in a ubiquitin-dependent manner into motile and reversible proteasome storage granules (PSGs) in the cytoplasm. In cancer cells upon amino acid deprivation, heat shock, osmotic stress, oxidative stress, or the inhibition of either proteasome activity or nuclear export, reversible proteasome foci containing poly-ubiquitinated substrates are formed by liquid-liquid phase separation in the nucleus. In this review, we summarize recent literature revealing new links between nuclear transport, ubiquitin signaling and the intracellular organization of proteasomes during cellular stress conditions.