Proteasomes are key proteases in regulating protein homeostasis. Their holo-enzymes are composed of multiple subunits arranged in a proteolytically active core and a regulatory particle. Proteasomal proteolysis is essential for the degradation of defective translation products and short-lived proteins which control time-sensitive cellular processes like cell cycle progression. Failures in degrading these proteins can result in cell cycle arrest and the accumulation of cytotoxic protein aggregates. With the decline of proteasome activities during aging, protein aggregations menace an early onset of neurodegenerative diseases.

Using in vivo and in vitro localization studies proteasomes were primarily observed in the nucleus of highly proliferating cells suggesting that proteasomal degradation mainly takes place inside the nucleus.

Proteasomes were also found close to the endoplasmic reticulum, decorating the nuclear pore complex and clustered around cytotoxic protein aggregations, where proteasomes attempt to degrade aberrant proteins.

The targeting mechanism of proteasomes to different cellular compartments is one of the least explored but most challenging topics in the proteasome field. As the second most abundant protein complex in the cell, almost forty different proteasomal subunits are continuously synthesized and assembled into inactive precursor complexes. Either precursor complexes or holo-enzymes can be imported into the nucleus suggesting that several nuclear import pathways exist.

If cells are deprived of nutrients, proteasomes seem to be more cytosolic than nuclear. How proteasomes are exported from the nucleus into the cytoplasm is unknown. Moreover, proteasomal substrates shuttle between the nucleo- and cytoplasm which adds another layer of complexity to the question of where proteasomal substrates are finally degraded.

In non-dividing yeast cells, proteasomes are sequestered into motile and reversible cytoplasmic storage granules which protect proteasomes from autophagy and lysosomal elimination. In neuronal cells, proteasomes are transported along axons and sequestered into motile granules upon synaptic stimulation.

This collection of articles will draw attention to the current knowledge on intracellular proteasome dynamics and to prevailing questions for future research.

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