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Intracellular Dynamics of the Ubiquitin-Proteasome-System.

Chowdhury M, Enenkel C - F1000Res (2015)

Bottom Line: Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm.Most of our current knowledge is based on studies in yeast.Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells which comprise the majority of our body's cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.

ABSTRACT
The ubiquitin-proteasome system is the major degradation pathway for short-lived proteins in eukaryotic cells. Targets of the ubiquitin-proteasome-system are proteins regulating a broad range of cellular processes including cell cycle progression, gene expression, the quality control of proteostasis and the response to geno- and proteotoxic stress. Prior to degradation, the proteasomal substrate is marked with a poly-ubiquitin chain. The key protease of the ubiquitin system is the proteasome. In dividing cells, proteasomes exist as holo-enzymes composed of regulatory and core particles. The regulatory complex confers ubiquitin-recognition and ATP dependence on proteasomal protein degradation. The catalytic sites are located in the proteasome core particle. Proteasome holo-enzymes are predominantly nuclear suggesting a major requirement for proteasomal proteolysis in the nucleus. In cell cycle arrested mammalian or quiescent yeast cells, proteasomes deplete from the nucleus and accumulate in granules at the nuclear envelope (NE) / endoplasmic reticulum (ER) membranes. In prolonged quiescence, proteasome granules drop off the NE / ER membranes and migrate as stable organelles throughout the cytoplasm, as thoroughly investigated in yeast. When quiescence yeast cells are allowed to resume growth, proteasome granules clear and proteasomes are rapidly imported into the nucleus. Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm. Most of our current knowledge is based on studies in yeast. Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells which comprise the majority of our body's cells.

No MeSH data available.


Related in: MedlinePlus

Blm10-dependent nuclear import of mature CP.In quiescent yeast cells mature CP is stored in reversible and motile granules in the cytoplasm, which rapidly clear with the resumption of growth. Blm10 mediates the nuclear import of mature CP.
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f4: Blm10-dependent nuclear import of mature CP.In quiescent yeast cells mature CP is stored in reversible and motile granules in the cytoplasm, which rapidly clear with the resumption of growth. Blm10 mediates the nuclear import of mature CP.

Mentions: Though the CP and RP co-localize in the PSG, they seem to be loosely associated. Conflicting reports exist about the stability of RP-CP assemblies in lysates of quiescent cells (Bajoreket al., 2003;Hannaet al., 2012;Weberrusset al., 2013). The finding that RP-CP assemblies are less stable coincides with the decline in ATP during quiescence as well as the reduced proclivity of the proteasome to degrade poly-ubiquitinated substrate. Instead of an association of the CP with the RP, most CP is seen interacting with Blm10, a conserved 240 kDa HEAT repeat protein (Weberrusset al., 2013). Upon exit from quiescence, the PSGs rapidly clear and mature proteasomes are imported into the nucleus within a few minutes. The imported proteasomes must be matured and assembled, as time does not permit the new synthesis of precursor complexes (Laporteet al., 2008). Here, Blm10 plays an important role and represents the first characterized nuclear transporter which particularly facilitates nuclear import of mature CP (Figure 4). Quiescentblm10Δ mutants exhibit a significant delay in resuming cell growth due to the deficit in mature CP in the nucleus. Furthermore, Blm10 binds FG-Nups and GTP-bound Ran and dissociates from the CP upon interaction with RanGTP, suggesting that Blm10 shares functional similarities with Kap95, the classical importin β (Weberrusset al., 2013). Along this line, Blm10 belongs to the HEAT repeat family with α-solenoid fold, a structural feature shared by β karyopherins/importins (Huber & Groll, 2012). During cell proliferation, Blm10 is also expressed but to a much lesser extent (Weberrusset al., 2013). Only a minor fraction of the CP, pre-holo-CP and CP precursor complexes is associated with Blm10 in growing yeast. The Blm10-bound fraction significantly increases under geno-and proteotoxic stress suggesting a high demand for nuclear proteasomes under these growth conditions (Dohertyet al., 2012;Fehlkeret al., 2003;Lehmannet al., 2008). Since Blm10 associates with constitutively open or disordered CP α rings, Blm10 also plays a role in regulating α-ring gating during CP maturation (Lehmannet al., 2008). The wider α ring conformation of CP-precursor complexes seems to be preferentially bound to Blm10 and importin αβ by representing import intermediates. Thus, the Blm10-dependent import pathway complements the canonical nuclear import pathway.


Intracellular Dynamics of the Ubiquitin-Proteasome-System.

Chowdhury M, Enenkel C - F1000Res (2015)

Blm10-dependent nuclear import of mature CP.In quiescent yeast cells mature CP is stored in reversible and motile granules in the cytoplasm, which rapidly clear with the resumption of growth. Blm10 mediates the nuclear import of mature CP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544378&req=5

f4: Blm10-dependent nuclear import of mature CP.In quiescent yeast cells mature CP is stored in reversible and motile granules in the cytoplasm, which rapidly clear with the resumption of growth. Blm10 mediates the nuclear import of mature CP.
Mentions: Though the CP and RP co-localize in the PSG, they seem to be loosely associated. Conflicting reports exist about the stability of RP-CP assemblies in lysates of quiescent cells (Bajoreket al., 2003;Hannaet al., 2012;Weberrusset al., 2013). The finding that RP-CP assemblies are less stable coincides with the decline in ATP during quiescence as well as the reduced proclivity of the proteasome to degrade poly-ubiquitinated substrate. Instead of an association of the CP with the RP, most CP is seen interacting with Blm10, a conserved 240 kDa HEAT repeat protein (Weberrusset al., 2013). Upon exit from quiescence, the PSGs rapidly clear and mature proteasomes are imported into the nucleus within a few minutes. The imported proteasomes must be matured and assembled, as time does not permit the new synthesis of precursor complexes (Laporteet al., 2008). Here, Blm10 plays an important role and represents the first characterized nuclear transporter which particularly facilitates nuclear import of mature CP (Figure 4). Quiescentblm10Δ mutants exhibit a significant delay in resuming cell growth due to the deficit in mature CP in the nucleus. Furthermore, Blm10 binds FG-Nups and GTP-bound Ran and dissociates from the CP upon interaction with RanGTP, suggesting that Blm10 shares functional similarities with Kap95, the classical importin β (Weberrusset al., 2013). Along this line, Blm10 belongs to the HEAT repeat family with α-solenoid fold, a structural feature shared by β karyopherins/importins (Huber & Groll, 2012). During cell proliferation, Blm10 is also expressed but to a much lesser extent (Weberrusset al., 2013). Only a minor fraction of the CP, pre-holo-CP and CP precursor complexes is associated with Blm10 in growing yeast. The Blm10-bound fraction significantly increases under geno-and proteotoxic stress suggesting a high demand for nuclear proteasomes under these growth conditions (Dohertyet al., 2012;Fehlkeret al., 2003;Lehmannet al., 2008). Since Blm10 associates with constitutively open or disordered CP α rings, Blm10 also plays a role in regulating α-ring gating during CP maturation (Lehmannet al., 2008). The wider α ring conformation of CP-precursor complexes seems to be preferentially bound to Blm10 and importin αβ by representing import intermediates. Thus, the Blm10-dependent import pathway complements the canonical nuclear import pathway.

Bottom Line: Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm.Most of our current knowledge is based on studies in yeast.Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells which comprise the majority of our body's cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.

ABSTRACT
The ubiquitin-proteasome system is the major degradation pathway for short-lived proteins in eukaryotic cells. Targets of the ubiquitin-proteasome-system are proteins regulating a broad range of cellular processes including cell cycle progression, gene expression, the quality control of proteostasis and the response to geno- and proteotoxic stress. Prior to degradation, the proteasomal substrate is marked with a poly-ubiquitin chain. The key protease of the ubiquitin system is the proteasome. In dividing cells, proteasomes exist as holo-enzymes composed of regulatory and core particles. The regulatory complex confers ubiquitin-recognition and ATP dependence on proteasomal protein degradation. The catalytic sites are located in the proteasome core particle. Proteasome holo-enzymes are predominantly nuclear suggesting a major requirement for proteasomal proteolysis in the nucleus. In cell cycle arrested mammalian or quiescent yeast cells, proteasomes deplete from the nucleus and accumulate in granules at the nuclear envelope (NE) / endoplasmic reticulum (ER) membranes. In prolonged quiescence, proteasome granules drop off the NE / ER membranes and migrate as stable organelles throughout the cytoplasm, as thoroughly investigated in yeast. When quiescence yeast cells are allowed to resume growth, proteasome granules clear and proteasomes are rapidly imported into the nucleus. Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm. Most of our current knowledge is based on studies in yeast. Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells which comprise the majority of our body's cells.

No MeSH data available.


Related in: MedlinePlus