Ras Protein/cAMP-dependent Protein Kinase Signaling Is Negatively Regulated by a Deubiquitinating Enzyme, Ubp3, in Yeast

Li, Yang; Wang, Yuqi

doi:10.1074/jbc.m112.449751

Cited by 23 publications

(16 citation statements)

References 61 publications

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“…Recently, it was reported that cAMP levels are elevated in ubp3∆ mutants leading to hyper‐activation of the PKA signaling pathway and that overexpression of PDE2 , a phosphodiesterase that hydrolyzes cAMP, counteracts some phenotypes typical of cells lacking UBP3 (Li & Wang, ). Therefore, we tested whether overexpression of PDE2 could suppress the prolonged deposition of Ssa2‐GFP in JUNQ seen in ubp3∆ mutants.…”

Section: Resultsmentioning

confidence: 99%

Opposing roles of Ubp3-dependent deubiquitination regulate replicative life span and heat resistance

Öling

Eisele²,

Kvint³

et al. 2014

The EMBO Journal

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The interplay between molecular chaperones, ubiquitin/deubiquitinating enzymes, and proteasomes is a critical element in protein homeostasis. Among these factors, the conserved deubiquitinase, Ubp3, has the interesting ability, when overproduced, to suppress the requirement for the major cytosolic Hsp70 chaperones. Here, we show that Ubp3 overproduction counteracts deficiency of Hsp70s by the removal of damaged proteins deposited in inclusion bodies (JUNQ) during both aging and heat stress. Consistent with this, Ubp3 destabilized, deubiquitinated, and diminished the toxicity of the JUNQ-associated misfolded protein Ubc9(ts) in a proteasome-dependent manner. In contrast, another misfolded model protein, ssCPY*, was stabilized by Ubp3-dependent deubiquitination demonstrating a dual role for Ubp3, saving or destroying aberrant protein species depending on the stage at which the damaged protein is committed for destruction. We present genetic evidence for the former of these activities being key to Ubp3-dependent suppression of heat sensitivity in Hsp70-deficient cells, whereas protein destruction suppresses accelerated aging. We discuss the data in view of how heat stress and aging might elicit differential damage and challenges on the protein homeostasis network.

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Section: Resultsmentioning

confidence: 99%

Opposing roles of Ubp3-dependent deubiquitination regulate replicative life span and heat resistance

Öling

Eisele²,

Kvint³

et al. 2014

The EMBO Journal

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“…UBP3 could deubiquitinate many different substrates. Indeed, previous studies have demonstrated roles for Ubp3 in enhancing or delaying the degradation of particular substrates by direct deubiquitination (Brew and Huffaker 2002;Cohen et al 2003a;Kraft et al 2008;Kvint et al 2008;Chew et al 2010;Li and Wang 2013). Ubp3 could also affect the proteasome itself.…”

Section: Discussionmentioning

confidence: 99%

The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance

et al. 2016

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Aneuploidy-or an unbalanced karyotype in which whole chromosomes are gained or lost-causes reduced fitness at both the cellular and organismal levels but is also a hallmark of human cancers. Aneuploidy causes a variety of cellular stresses, including genomic instability, proteotoxic and oxidative stresses, and impaired protein trafficking. The deubiquitinase Ubp3, which was identified by a genome-wide screen for gene deletions that impair the fitness of aneuploid yeast, is a key regulator of aneuploid cell homeostasis. We show that deletion of UBP3 exacerbates both karyotype-specific phenotypes and global stresses of aneuploid cells, including oxidative and proteotoxic stress. Indeed, Ubp3 is essential for proper proteasome function in euploid cells, and deletion of this deubiquitinase leads to further proteasome-mediated proteotoxicity in aneuploid yeast. Notably, the importance of UBP3 in aneuploid cells is conserved. Depletion of the human homolog of UBP3, USP10, is detrimental to the fitness of human cells upon chromosome missegregation, and this fitness defect is accompanied by autophagy inhibition. We thus used a genome-wide screen in yeast to identify a guardian of aneuploid cell fitness conserved across species. We propose that interfering with Ubp3/USP10 function could be a productive avenue in the development of novel cancer therapeutics.

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“…Upon Ras1 activation, Ras1-GTP binds to AC and catalyzes production of the second messenger cAMP. Subsequently, the increase of intracellular cAMP activates cAMP-dependent PKA that phosphorylates a series of transcription factors that control phenotype, metabolism, stress adaption, proliferation, and other functions (Broach, 1991 ; Rolland et al, 2002 ; Cassola et al, 2004 ; Li and Wang, 2013 ). Further studies show that Efg1, a transcription factor, in parallel with other unidentified signaling molecules, is the terminal point of the Ras1-cAMP-PKA pathway in C. albicans (Bockmühl and Ernst, 2001 ; Shapiro et al, 2009 ).…”

Section: Potential Antifungal Targets Within Hsps-associated Intracelmentioning

confidence: 99%

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

Gong

et al. 2017

Front. Cell. Infect. Microbiol.

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In recent decades, the incidence of invasive fungal infections has increased notably. Candida albicans (C. albicans), a common opportunistic fungal pathogen that dwells on human mucosal surfaces, can cause fungal infections, especially in immunocompromised and high-risk surgical patients. In addition, the wide use of antifungal agents has likely contributed to resistance of C. albicans to traditional antifungal drugs, increasing the difficulty of treatment. Thus, it is urgent to identify novel antifungal drugs to cope with C. albicans infections. Heat shock proteins (Hsps) exist in most organisms and are expressed in response to thermal stress. In C. albicans, Hsps control basic physiological activities or virulence via interaction with a variety of diverse regulators of cellular signaling pathways. Moreover, it has been demonstrated that Hsps confer drug resistance to C. albicans. Many studies have shown that disrupting the normal functions of C. albicans Hsps inhibits fungal growth or reverses the tolerance of C. albicans to traditional antifungal drugs. Here, we review known functions of the diverse Hsp family, Hsp-associated intracellular signaling pathways and potential antifungal targets based on these pathways in C. albicans. We hope this review will aid in revealing potential new roles of C. albicans Hsps in addition to canonical heat stress adaptions and provide more insight into identifying potential novel antifungal targets.

show abstract

Ras Protein/cAMP-dependent Protein Kinase Signaling Is Negatively Regulated by a Deubiquitinating Enzyme, Ubp3, in Yeast

Cited by 23 publications

References 61 publications

Opposing roles of Ubp3-dependent deubiquitination regulate replicative life span and heat resistance

Opposing roles of Ubp3-dependent deubiquitination regulate replicative life span and heat resistance

The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

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