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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

Nuclear import of CP precursor complexes by the classical importin/karyopherin αβ pathway in proliferating yeast.The α rings with the classical NLS are depicted in red. The β rings with propeptides are depicted in blue. The CP-dedicated chaperone and maturation factor Ump1 is depicted in yellow. The completion of CP maturation occurs in the nucleus with the degradation of Ump1.
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f1: Nuclear import of CP precursor complexes by the classical importin/karyopherin αβ pathway in proliferating yeast.The α rings with the classical NLS are depicted in red. The β rings with propeptides are depicted in blue. The CP-dedicated chaperone and maturation factor Ump1 is depicted in yellow. The completion of CP maturation occurs in the nucleus with the degradation of Ump1.

Mentions: Our studies in yeast strongly suggest that newly synthesized proteasomes are imported from the cytosol into the nucleus as inactive precursor complexes and that the maturation of nuclear CP proceeds to completion post-import (Lehmannet al., 2002). Although electron microscopy studies have shown that the NPC could expand to accommodate the longitudinal passage of the 30S proteasome, the permeability barriers towards macromolecules such as CP precursor complexes and RP assembly modules must be overcome by specific importins/karyopherins (Pante & Kann, 2002). Several classical NLSs exist within the N-termini of distinct α subunits which were proposed to be either accessible rendering the CP in an import-competent conformation, or to be masked rendering the CP in an import-incompatible conformation (Tanakaet al., 1990). Indeed, recent cryo-EM structure analysis revealed flexible and less structured α ring surfaces in Ump1-associated CP precursor complexes (Kocket al., 2015), in compliance with our finding that importin α recognizes CP precursor complexes but not mature CP with closed α rings (Lehmannet al., 2002). Our model upon which CP precursor complexes are imported into the nucleus was supported by the following observations (Figure 1). First, when tagged with GFP, Ump1 is predominantly nuclear in spite of the fact that CP precursor complexes are assembled from nascent subunits in the cytoplasm. Second, in importin α mutants namelysrp1-49 but not insrp1-31, several groups found that the CP is mislocalized to the cytoplasm, providing another piece of evidence for the classical import pathway of proteasomes. Unprocessed and incompletely processed β5 subunits, crucial determinants of CP precursor complexes and pre-holo-CP, respectively, accumulate insrp1-49 mutants, while precursors of β5 subunits are hardly detectable in wild type cells (Lehmannet al., 2002). Third, when CP maturation is delayed byUMP1 deletion, all CP reporter proteins accumulate in the nucleus, although half of the CP is not fully matured and most likely exists as pre-holo-CP (Fehlkeret al., 2003;Lehmannet al., 2008).


Intracellular Dynamics of the Ubiquitin-Proteasome-System.

Chowdhury M, Enenkel C - F1000Res (2015)

Nuclear import of CP precursor complexes by the classical importin/karyopherin αβ pathway in proliferating yeast.The α rings with the classical NLS are depicted in red. The β rings with propeptides are depicted in blue. The CP-dedicated chaperone and maturation factor Ump1 is depicted in yellow. The completion of CP maturation occurs in the nucleus with the degradation of Ump1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Nuclear import of CP precursor complexes by the classical importin/karyopherin αβ pathway in proliferating yeast.The α rings with the classical NLS are depicted in red. The β rings with propeptides are depicted in blue. The CP-dedicated chaperone and maturation factor Ump1 is depicted in yellow. The completion of CP maturation occurs in the nucleus with the degradation of Ump1.
Mentions: Our studies in yeast strongly suggest that newly synthesized proteasomes are imported from the cytosol into the nucleus as inactive precursor complexes and that the maturation of nuclear CP proceeds to completion post-import (Lehmannet al., 2002). Although electron microscopy studies have shown that the NPC could expand to accommodate the longitudinal passage of the 30S proteasome, the permeability barriers towards macromolecules such as CP precursor complexes and RP assembly modules must be overcome by specific importins/karyopherins (Pante & Kann, 2002). Several classical NLSs exist within the N-termini of distinct α subunits which were proposed to be either accessible rendering the CP in an import-competent conformation, or to be masked rendering the CP in an import-incompatible conformation (Tanakaet al., 1990). Indeed, recent cryo-EM structure analysis revealed flexible and less structured α ring surfaces in Ump1-associated CP precursor complexes (Kocket al., 2015), in compliance with our finding that importin α recognizes CP precursor complexes but not mature CP with closed α rings (Lehmannet al., 2002). Our model upon which CP precursor complexes are imported into the nucleus was supported by the following observations (Figure 1). First, when tagged with GFP, Ump1 is predominantly nuclear in spite of the fact that CP precursor complexes are assembled from nascent subunits in the cytoplasm. Second, in importin α mutants namelysrp1-49 but not insrp1-31, several groups found that the CP is mislocalized to the cytoplasm, providing another piece of evidence for the classical import pathway of proteasomes. Unprocessed and incompletely processed β5 subunits, crucial determinants of CP precursor complexes and pre-holo-CP, respectively, accumulate insrp1-49 mutants, while precursors of β5 subunits are hardly detectable in wild type cells (Lehmannet al., 2002). Third, when CP maturation is delayed byUMP1 deletion, all CP reporter proteins accumulate in the nucleus, although half of the CP is not fully matured and most likely exists as pre-holo-CP (Fehlkeret al., 2003;Lehmannet al., 2008).

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