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

Journal article
Authors David Öling
Frederik Eisele
Kristian Kvint
Thomas Nyström
Published in Embo Journal
Volume 33
Issue 7
Pages 747-761
ISSN 0261-4189
Publication year 2014
Published at Department of Chemistry and Molecular Biology
Pages 747-761
Language en
Links dx.doi.org/10.1002/embj.201386822
Keywords SSA1 SSA2, heat stress, aging, Ubp3, protein aggregates, SACCHAROMYCES-CEREVISIAE, UBIQUITIN PROTEASE, AGGREGATED PROTEINS, MISFOLDED PROTEINS, 2-DIMENSIONAL GELS, QUALITY-CONTROL, YEAST, DEGRADATION, UBP3, HSP70
Subject categories Chemical Sciences

Abstract

Abstract 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, increment 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. The conserved deubiquitinase Ubp3 regulates both heat stress resistance and replicative life span in yeast through dual roles in cellular protein homeostasis. Ubp3 aids removal of damaged proteins either by stabilizing them in a rescue pathway or by accelerating their proteasome-mediated degradation. Ubp3 promotes the removal of damaged proteins deposited in JUNQ inclusion bodies. Misfolded model proteins are either stabilized or degraded by Ubp3 overproduction. Ubp3 suppresses heat sensitivity in Hsp70-deficient cells by diverting damaged proteins from destruction. Ubp3-mediated proteasomal degradation of cytotoxic proteins suppresses accelerated replicative aging.

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Denna text är utskriven från följande webbsida:
http://www.gu.se/english/research/publication/?publicationId=197728
Utskriftsdatum: 2019-08-22