Abstract
Proteasomes are highly conserved protease complexes responsible for the degradation of aberrant and short-lived proteins. In highly proliferating yeast and mammalian cells, proteasomes are predominantly nuclear. During quiescence and cell cycle arrest, proteasomes accumulate in granules in close proximity to the nuclear envelope/ER. With prolonged quiescence in yeast, these proteasome granules pinch off as membraneless organelles, and migrate as stable entities through the cytoplasm. Upon exit from quiescence, the proteasome granules clear and the proteasomes are rapidly transported into the nucleus, a process reflecting the dynamic nature of these multisubunit complexes. Due to the scarcity of studies on the nuclear transport of mammalian proteasomes, we summarised the current knowledge on the nuclear import of yeast proteasomes. This pathway uses canonical nuclear localisation signals within proteasomal subunits and Srp1/Kap95, and the canonical import receptor, named importin/karyopherin αβ. Blm10, a conserved 240 kDa protein, which is structurally related to Kap95, provides an alternative import pathway. Two models exist upon which either inactive precursor complexes or active holo-enzymes serve as the import cargo. Here, we reconcile both models and suggest that the import of inactive precursor complexes predominates in dividing cells, while the import of mature enzymes mainly occurs upon exit from quiescence.
Highlights
Proteostasis is defined as a series of biological processes that work in concert to create and maintain a functional proteome in a living cell
We have summarised the literature covering the nuclear import of yeast proteasomes
Since only a few in vitro studies using reconstitution systems for mammalian proteasomes are known from the 1990s, we restricted our discussions to the nuclear import pathways of yeast proteasomes
Summary
Proteostasis is defined as a series of biological processes that work in concert to create and maintain a functional proteome in a living cell. Yeast, a prime model organism of eukaryotic cells, proved to be suited for GFP-labelling techniques, since endogenous proteins can be functionally replaced by their GFP-tagged versions using homologous recombination into the chromosomal locus. Without previous limitations given by ambiguous antibodies and fixation conditions used for indirect detection methods, live cell imaging revealed a substantial localisation of GFP-tagged proteasomes within the nucleus throughout the cell cycle in yeast [12,13,14,15]. Cultured mammalian cells arrested in cell cycle progression by proteasome inhibition show proteasome granules as well, suggesting a conserved mechanism underlying their organisation. Few studies exist in primary cell lines of neurons expressing GFP-labelled proteasomes Their dendrites harbour multiple motile proteasome granules, suggesting that proteasome granules exist in non-dividing mammalian cells, which essentially comprise the minority of our body’s cells [34]. In somatic cells of higher eukaryotes, the NE completely disassembles and reassembles during open mitosis, allowing alternative nuclear uptake mechanisms for proteasomes
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