Fission Yeast 26S Proteasome Mutants Are Multi-Drug Resistant Due to Stabilization of the Pap1 Transcription Factor

Penney, Mary; Samejima, Itaru; Wilkinson, Caroline R.M.; McInerny, Christopher; Mathiassen, Søs Grønbæk; Wallace, Mark N.; Toda, Takashi; Hartmann‐Petersen, Rasmus; Gordon, Colin

doi:10.1371/journal.pone.0050796

Cited by 10 publications

(12 citation statements)

References 52 publications

(19 reference statements)

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“…Oxidative stress is known to activate the stress-activated kinases p38-MAPK and JNK through ASK1 (16,29), and these pathways are known to be induced by proteasome inhibitors (25,65). Further, yeast strains carrying mutations in 26S proteasome subunits overexpress Pap1, the Schizosaccharomyces pombe homolog of the human AP-1 transcription factor (48). We indeed found activation of both p38-MAPK and JNK by b-AP15.…”

Section: Discussionmentioning

confidence: 52%

Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress

Brnjic

Mazurkiewicz

Fryknäs

et al. 2014

Antioxidants & Redox Signaling

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Section: Discussionmentioning

confidence: 52%

Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress

Brnjic

Mazurkiewicz

Fryknäs

et al. 2014

Antioxidants & Redox Signaling

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“…Recently, it has been demonstrated that the stabilisation of Pap1 in proteasome mutants of Schizosaccharomyces pombe increases resistance to oxidative stress [43]. We can generalise the idea that the proteasome may play a negative role in the stress response pathways that have transcription regulators as proteasome substrates.…”

Section: Discussionmentioning

confidence: 92%

Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4‐dependent DNA repair genes

Карпов¹,

Spasskaya²,

Tutyaeva³

et al. 2013

FEBS Letters

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Edited by Ivan SadowskiKeywords: Yeast DNA damage response Proteasome Rpn4 RAD52 a b s t r a c t The 26S proteasome is an ATP-dependent multi-subunit protease complex and the major regulator of intracellular protein turnover and quality control. However, its role in the DNA damage response is controversial. We addressed this question in yeast by disrupting the transcriptional regulation of the PRE1 proteasomal gene. The mutant strain has decreased proteasome activity and is hyper-resistant to various DNA-damaging agents. We found that Rpn4-target genes MAG1, RAD23, and RAD52 are overexpressed in this strain due to Rpn4 stabilisation. These genes represent three different pathways of base excision, nucleotide excision and double strand break repair by homologous recombination (DSB-HR). Consistently, the proteasome mutant displays increased DSB-HR activity. Our data imply that the proteasome may have a negative role in DNA damage response.

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“…The ubiquitylation of Sec3-913-V5 was determined by precipitating His 6 -ubiquitin under denaturing conditions (in 8 M urea), followed by electrophoresis and blotting for the V5 tag on Sec3-913 as described previously (80).…”

Section: Ubiquitylation Of Sec3-913mentioning

confidence: 99%

The exocyst subunit Sec3 is regulated by a protein quality control pathway

Kampmeyer

Karakostova

Schenstrøm

et al. 2017

Journal of Biological Chemistry

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Exocytosis involves fusion of secretory vesicles with the plasma membrane, thereby delivering membrane proteins to the cell surface and releasing material into the extracellular space. The tethering of the secretory vesicles before membrane fusion is mediated by the exocyst, an essential phylogenetically conserved octameric protein complex. Exocyst biogenesis is regulated by several processes, but the mechanisms by which the exocyst is degraded are unknown. Here, to unravel the components of the exocyst degradation pathway, we screened for extragenic suppressors of a temperature-sensitive fission yeast strain mutated in the exocyst subunit Sec3 (). One of the suppressing DNAs encoded a truncated dominant-negative variant of the 26S proteasome subunit, Rpt2, indicating that exocyst degradation is controlled by the ubiquitin-proteasome system. The temperature-dependent growth defect of the strain was gene dosage-dependent and suppressed by blocking the proteasome, Hsp70-type molecular chaperones, the Pib1 E3 ubiquitin-protein ligase, and the deubiquitylating enzyme Ubp3. Moreover, defects in cell septation, exocytosis, and endocytosis in mutant strains were similarly alleviated by mutation of components in this pathway. We also found that, particularly under stress conditions, wild-type Sec3 degradation is regulated by Pib1 and the 26S proteasome. In conclusion, our results suggest that a cytosolic protein quality control pathway monitors folding and proteasome-dependent turnover of an exocyst subunit and, thereby, controls exocytosis in fission yeast.

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Fission Yeast 26S Proteasome Mutants Are Multi-Drug Resistant Due to Stabilization of the Pap1 Transcription Factor

Cited by 10 publications

References 52 publications

Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress

Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress

Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4‐dependent DNA repair genes

The exocyst subunit Sec3 is regulated by a protein quality control pathway

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