Dataset Information

Different Expression Levels of Human Mutant Ubiquitin B⁺¹ (UBB⁺¹) Can Modify Chronological Lifespan or Stress Resistance of Saccharomyces cerevisiae.

ABSTRACT: The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). UBB⁺¹, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB⁺¹ to evaluate its effects on proteasome function and cell death, particularly under conditions of chronological aging. We showed that the expression of UBB⁺¹ caused inhibition of the three proteasomal proteolytic activities (caspase-like (?1), trypsin-like (?2) and chymotrypsin-like (?5) activities) in yeast. Interestingly, this inhibition did not alter cell viability of growing cells. Moreover, we showed that cells expressing UBB⁺¹ at lower level displayed an increased capacity to degrade induced misfolded proteins. When we evaluated cells during chronological aging, UBB⁺¹ expression at lower level, prevented cells to accumulate reactive oxygen species (ROS) and avert apoptosis, dramatically increasing yeast life span. Since proteasome inhibition by UBB⁺¹ has previously been shown to induce chaperone expression and thus protect against stress, we evaluated our UBB⁺¹ model under heat shock and oxidative stress. Higher expression of UBB⁺¹ caused thermotolerance in yeast due to induction of chaperones, which occurred to a lesser extent at lower expression level of UBB⁺¹ (where we observed the phenotype of extended life span). Altering UPS capacity by differential expression of UBB⁺¹ protects cells against several stresses during chronological aging. This system can be valuable to study the effects of UBB⁺¹ on misfolded proteins involved in neurodegeneration and aging.

SUBMITTER: Munoz-Arellano AJ

PROVIDER: S-EPMC6008557 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Different Expression Levels of Human Mutant Ubiquitin B+1 (UBB+1) Can Modify Chronological Lifespan or Stress Resistance of Saccharomyces cerevisiae.

Muñoz-Arellano Ana Joyce AJ Chen Xin X Molt Andrea A Meza Eugenio E Petranovic Dina D

Frontiers in molecular neuroscience 20180608

The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). UBB+1, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB+1</ ...[more]

PMID: 29950972

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Project description:We have performed a comprehensive analysis of the involvement of histone H3 and H4 residues in the regulation of chronological lifespan in yeast and identify four structural groups in the nucleosome that influence lifespan. We also identify residues where substitution with an epigenetic mimic extends lifespan, providing evidence that a simple epigenetic switch, without possible additional background modifications, causes longevity. Residues where substitution result in the most pronounced lifespan extension are all on the exposed face of the nucleosome, with the exception of H3E50, which is present on the lateral surface, between two DNA gyres. Other residues that have a more modest effect on lifespan extension are concentrated at the extremities of the H3-H4 dimer, suggesting a role in stabilizing the dimer in its nucleosome frame. Residues that reduce lifespan are buried in the histone handshake motif, suggesting that these mutations destabilize the octamer structure. All residues exposed on the nucleosome disk face and that cause lifespan extension are known to interact with Sir3. We find that substitution of H4K16 and H4H18 cause Sir3 to redistribute from telomeres and silent mating loci to secondary positions, often enriched for Rap1, Abf1 or Reb1 binding sites, whereas H3E50 does not. The redistribution of Sir3 in the genome can be reproduced by an equilibrium model based on primary and secondary binding sites with different affinities for Sir3. The redistributed Sir3 cause transcriptional repression at most of the new loci, including of genes where null mutants were previously shown to extend chronological lifespan. The transcriptomic profiles of H4K16 and H4H18 mutant strains are very similar, and compatible with a DNA replication stress response. This is distinct from the transcriptomic profile of H3E50, which matches strong induction of oxidative phosphorylation. We propose that the different groups of residues are involved in binding to heterochromatin proteins, in destabilizing the association of the nucleosome DNA, disrupting binding of the H3-H4 dimer in the nucleosome, or disrupting the structural stability of the octamer, each category impacting on chronological lifespan by a different mechanism.

Dataset Information

Different Expression Levels of Human Mutant Ubiquitin B⁺¹ (UBB⁺¹) Can Modify Chronological Lifespan or Stress Resistance of Saccharomyces cerevisiae.

Publications

Different Expression Levels of Human Mutant Ubiquitin B<sup>+1</sup> (UBB<sup>+1</sup>) Can Modify Chronological Lifespan or Stress Resistance of <i>Saccharomyces cerevisiae</i>.

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