Protein quality control in the nucleus

Jones, Ramon D.; Gardner, Richard G.

doi:10.1016/j.ceb.2016.03.002

Cited by 30 publications

(20 citation statements)

References 111 publications

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“…The UPS plays well-characterized and critical roles in protein QC at the endoplasmic reticulum (ER), ribosome, nucleus, and cytosol ( Brandman and Hegde 2016 ; Jones and Gardner 2016 ; Defenouillere and Fromont-Racine 2017 ; Preston and Brodsky 2017 ). Recent studies have revealed a role for the UPS in QC at mitochondria as well ( Braun and Westermann 2017 ), but far less is known regarding the mechanisms or scope of this type of degradation.…”

Section: Resultsmentioning

confidence: 99%

The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of both Centromeric and Two-Micron Plasmids in Saccharomyces cerevisiae

Metzger

Scales

Dunklebarger

et al. 2017

G3 Genes|Genomes|Genetics

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Protein degradation by the ubiquitin-proteasome system is essential to many processes. We sought to assess its involvement in the turnover of mitochondrial proteins in Saccharomyces cerevisiae. We find that deletion of a specific ubiquitin ligase (E3), Psh1p, increases the abundance of a temperature-sensitive mitochondrial protein, mia40-4pHA, when it is expressed from a centromeric plasmid. Deletion of Psh1p unexpectedly elevates the levels of other proteins expressed from centromeric plasmids. Loss of Psh1p does not increase the rate of turnover of mia40-4pHA, affect total protein synthesis, or increase the protein levels of chromosomal genes. Instead, psh1Δ appears to increase the incidence of missegregation of centromeric plasmids relative to their normal 1:1 segregation. After generations of growth with selection for the plasmid, ongoing missegregation would lead to elevated plasmid DNA, mRNA, and protein, all of which we observe in psh1Δ cells. The only known substrate of Psh1p is the centromeric histone H3 variant Cse4p, which is targeted for proteasomal degradation after ubiquitination by Psh1p. However, Cse4p overexpression alone does not phenocopy psh1Δ in increasing plasmid DNA and protein levels. Instead, elevation of Cse4p leads to an apparent increase in 1:0 plasmid segregation events. Further, 2 μm high-copy yeast plasmids also missegregate in psh1Δ, but not when Cse4p alone is overexpressed. These findings demonstrate that Psh1p is required for the faithful inheritance of both centromeric and 2 μm plasmids. Moreover, the effects that loss of Psh1p has on plasmid segregation cannot be accounted for by increased levels of Cse4p.

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Section: Resultsmentioning

confidence: 99%

The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of both Centromeric and Two-Micron Plasmids in Saccharomyces cerevisiae

Metzger

Scales

Dunklebarger

et al. 2017

G3 Genes|Genomes|Genetics

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“…There is a rich literature about PQC in the ER and cytoplasm, but less is known about PQC in the nucleus. The UPS is the main mechanism for protein degradation in the nucleus ( Jones and Gardner, 2016 ; Gallagher et al, 2014 ; Shibata and Morimoto, 2014 ) and the nucleus harbors the majority of cellular proteasomes ( Wójcik and DeMartino, 2003 ; although see Dang et al, 2016 ). In yeast, the San1 ubiquitin ligase targets misfolded nuclear proteins for proteasomal degradation ( Gardner et al, 2005 ; Rosenbaum et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, the San1 ubiquitin ligase targets misfolded nuclear proteins for proteasomal degradation ( Gardner et al, 2005 ; Rosenbaum et al, 2011 ). Other ubiquitin ligases implicated in nuclear PQC include Ubr1, Doa10, and Asi, others are likely to exist ( Jones and Gardner, 2016 ). In addition to targeting misfolded nuclear proteins, some cytosolic proteins (i.e., polyQ-expanded proteins) are imported into the nucleus for degradation ( Park et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The Proline/Arginine Dipeptide from Hexanucleotide Repeat ExpandedC9ORF72Inhibits the Proteasome

Gupta

Lan

Mojsilovic-Petrovic

et al. 2017

eNeuro

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An intronic hexanucleotide repeat expansion (HRE) mutation in the C9ORF72 gene is the most common cause of familial ALS and frontotemporal dementia (FTD) and is found in ∼7% of individuals with apparently sporadic disease. Several different diamino acid peptides can be generated from the HRE by noncanonical translation (repeat-associated non-ATG translation, or RAN translation), and some of these peptides can be toxic. Here, we studied the effects of two arginine containing RAN translation products [proline/arginine repeated 20 times (PR20) and glycine/arginine repeated 20 times (GR20)] in primary rat spinal cord neuron cultures grown on an astrocyte feeder layer. We find that PR20 kills motor neurons with an LD50 of 2 µM, but in contrast to the effects of other ALS-causing mutant proteins (i.e., SOD or TDP43), PR20 does not evoke the biochemical signature of mitochondrial dysfunction, ER stress, or mTORC down-regulation. PR20 does result in a time-dependent build-up of ubiquitylated substrates, and this is associated with a reduction of flux through both autophagic and proteasomal degradation pathways. GR20, however, does not have these effects. The effects of PR20 on the proteasome are likely to be direct because (1) PR20 physically associates with proteasomes in biochemical assays, and (2) PR20 inhibits the degradation of a ubiquitylated test substrate when presented to purified proteasomes. Application of a proteasomal activator (IU1) blocks the toxic effects of PR20 on motor neuron survival. This work suggests that proteasomal activators have therapeutic potential in individuals with C9ORF72 HRE.

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“…Protein quality control has been studied in detail for certain cellular compartments, in particular the endoplasmic reticulum and cellular membrane 31 . In comparison, little is known about quality control of nuclear proteins, especially in mammalian cells 32 . Proteasomes are abundant in the nucleus, and are implicated in removing proteins that are misfolded due to polyglutamine expansion tracks found to cause neurological disorders such as Huntington’s and others 33 .…”

Section: Discussionmentioning

confidence: 99%

Reversible mislocalization of a disease-associated MRE11 splice variant product

Hartlerode

Regal

Ferguson

2018

Sci Rep

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Ataxia-telangiectasia (AT) and related disorders feature cancer predisposition, neurodegeneration, and immunodeficiency resulting from failure to respond to DNA damage. Hypomorphic mutations in MRE11 cause an AT-like disorder (ATLD) with variable clinical presentation. We have sought to understand how diverse MRE11 mutations may provide unique therapeutic opportunities, and potentially correlate with clinical variability. Here we have undertaken studies of an MRE11 splice site mutation that was found in two ATLD siblings that died of pulmonary adenocarcinoma at the young ages of 9 and 16. The mutation, termed MRE11 alternative splice mutation (MRE11ASM), causes skipping of a highly conserved exon while preserving the protein’s open reading frame. A new mouse model expressing Mre11ASM from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the MRE11ATLD1 mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11ASM is mislocalized to the cytoplasm, in contrast to MRE11ATLD1, which remains nuclear. Strikingly, MRE11ASM mislocalization is corrected by inhibition of the proteasome, implying that the protein undergoes strict protein quality control in the nucleus. These findings raise the prospect that inhibition of poorly understood nuclear protein quality control mechanisms might have therapeutic benefit in genetic disorders causing cytoplasmic mislocalization.

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Protein quality control in the nucleus

Cited by 30 publications

References 111 publications

The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of both Centromeric and Two-Micron Plasmids in Saccharomyces cerevisiae

The Ubiquitin Ligase (E3) Psh1p Is Required for Proper Segregation of both Centromeric and Two-Micron Plasmids in Saccharomyces cerevisiae

The Proline/Arginine Dipeptide from Hexanucleotide Repeat ExpandedC9ORF72Inhibits the Proteasome

Reversible mislocalization of a disease-associated MRE11 splice variant product

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