Ubr1 and Ubr2 Function in a Quality Control Pathway for Degradation of Unfolded Cytosolic Proteins

Nillegoda, Nadinath B.; Theodoraki, Maria A.; Mandal, A.; Mayo, Katie J.; Ren, Hong Yu; Sultana, Rasheda; Wu, Ken; Johnson, Jill L.; Cyr, Douglas M.; Caplan, Avrom J.

doi:10.1091/mbc.e10-02-0098

Cited by 125 publications

(156 citation statements)

References 56 publications

(86 reference statements)

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“…This study adds another layer of complexity to the known mechanisms of ERAD and underscores that previously accepted unidirectional pathways of ubiquitin-triggered degradation of proteins can intersect in a cell: the cytosolic ubiquitin ligase Ubr1 known to be involved in the quality control of cytosolic N-end rule substrates (47,48), as well as misfolded cytoplasmic proteins (25)(26)(27), now can be connected to ERAD (this study). On the other hand, the ERAD ligase Doa10, known mainly to facilitate degradation of ERAD substrates with a misfolded cytosolic domain, also ubiquitinates cytosolic N-acetylated substrates or substrates containing specific C-terminal appendages and targets them for degradation (49)(50)(51).…”

Section: Discussionmentioning

confidence: 58%

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Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation

Stolz

Besser

Hottmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Quality control and degradation of misfolded proteins are essential processes of all cells. The endoplasmic reticulum (ER) is the entry site of proteins into the secretory pathway in which protein folding occurs and terminally misfolded proteins are recognized and retrotranslocated across the ER membrane into the cytosol. Here, proteins undergo polyubiquitination by one of the membrane-embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome. In this study, we identify cytosolic Ubr1 (E3 ubiquitin ligase, N-recognin) as an additional ubiquitin ligase that can participate in ER-associated protein degradation (ERAD) in yeast. We show that two polytopic ERAD substrates, mutated transporter of the mating type a pheromone, Ste6* (sterile), and cystic fibrosis transmembrane conductance regulator, undergo Ubr1-dependent degradation in the presence and absence of the canonical ER ubiquitin ligases. Whereas in the case of Ste6* Ubr1 is specifically required under stress conditions such as heat or ethanol or in the absence of the canonical ER ligases, efficient degradation of human cystic fibrosis transmembrane conductance regulator requires function of Ubr1 already in wild-type cells under standard growth conditions. Together with the Hsp70 (heat shock protein) chaperone Ssa1 (stress-seventy subfamily A) and the AAA-type ATPase Cdc48 (cell division cycle), Ubr1 directs the substrate to proteasomal degradation. These data unravel another layer of complexity in ERAD.protein quality control | stress response | heat shock C onstantly occurring statistic folding errors, as well as misfolding due to stress such as heat, heavy metal ions, or oxygen require a rigorous protein quality control system in all cellular compartments. Irreversibly misfolded proteins are degraded by a selective proteolysis machinery, the ubiquitin proteasome system. In humans, impairment of the protein quality control and elimination system contributes to several severe diseases, including Parkinson disease, Alzheimer's disease, and CreutzfeldtJakob disease (1, 2), underscoring the importance of these quality control mechanisms. About one third of the cellular proteome consists of proteins passing the secretory pathway. Most of them are translocated into the endoplasmic reticulum (ER), where they are folded and permanently scanned for their functional structure. Only properly folded proteins are allowed to exit the ER and pass on to their site of action (3). Proteins that cannot fold properly are withdrawn from the secretory pathway, retrotranslocated across the ER membrane into the cytosol, polyubiquitinated and degraded by the 26S proteasome in a process termed ER-associated protein degradation (ERAD) (4).The eukaryotic model organism Saccharomyces cerevisiae has been a driving force in the discovery and elucidation of ERAD (4-10). It has been known for years that two polytopic ligases located in the ER membrane, Hrd1/Der3 (HMG-CoA reductas...

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Section: Discussionmentioning

confidence: 58%

“…Recently, the cytosolic RING (really interesting new gene) -type ubiquitin ligase Ubr1 was linked to ubiquitination and degradation of misfolded proteins in the cytosol (25)(26)(27). Therefore, we considered this ligase to ubiquitinate Ste6* in the absence of the canonical ERAD ligases.…”

Section: Significancementioning

confidence: 99%

Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation

Stolz

Besser

Hottmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…They include the nuclear quality control ligase San1 (Gardner et al 2005a) and the endoplasmic-reticulum-associated degradation E3s Hrd1 and Doa10 (see below). The principal quality control ligases in the cytoplasm appear to be Ubr1, Hul5, and the ribosome-bound ubiquitin ligase Rkr1/Ltn1 (Eisele and Wolf 2008;Bengtson and Joazeiro 2010;Heck et al 2010;Nillegoda et al 2010;Fang et al 2011). In addition, Ubr2 may contribute to removal of misfolded cytopasmic proteins (Nillegoda et al 2010).…”

Section: Quality-control Protein Degradationmentioning

confidence: 99%

The Ubiquitin–Proteasome System of Saccharomyces cerevisiae

et al. 2012

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Protein modifications provide cells with exquisite temporal and spatial control of protein function. Ubiquitin is among the most important modifiers, serving both to target hundreds of proteins for rapid degradation by the proteasome, and as a dynamic signaling agent that regulates the function of covalently bound proteins. The diverse effects of ubiquitylation reflect the assembly of structurally distinct ubiquitin chains on target proteins. The resulting ubiquitin code is interpreted by an extensive family of ubiquitin receptors. Here we review the components of this regulatory network and its effects throughout the cell.

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“…Proteasomal degradation of a protein in most cases requires polyubiquitination brought about by an enzyme system consisting of an ubiquitin activating enzyme E1, ubiquitinconjugating enzymes E2, and an ubiquitin ligase E3 (30,31), whereby the combination of the E2 and the E3 enzymes confer the specificity to the ubiquitination process. The ubiquitin ligase Ubr1 had recently been discovered by us (32) and others (33,34) as a ligase required for ubiquitinating misfolded proteins of the cytoplasm and of membrane localized ERAD substrates carrying their misfolded domain in the cytoplasm (35). Even though orphan Fas2 might not be a misfolded protein per se, we nevertheless tested the involvement of Ubr1 in the degradation process.…”

Section: Degradation Of Orphan Fas2 Is Triggered By the Ubiquitin Ligmentioning

confidence: 99%

Quality Control of a Cytoplasmic Protein Complex

Scazzari¹,

Amm²,

Wolf

2015

Journal of Biological Chemistry

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Background: Superfluous subunits of protein complexes are degraded to avoid unwanted erroneous reactions. Results: A machinery consisting of Hsp70, Cdc48, and components of the ubiquitin-proteasome system eliminates orphan fatty acid synthase subunit Fas2. Conclusion: Chaperone motors and the ubiquitin-proteasome system balance the homeostasis of the fatty acid synthase complex. Significance: Selective proteolysis is a tool to regulate protein complex stoichiometry.

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Ubr1 and Ubr2 Function in a Quality Control Pathway for Degradation of Unfolded Cytosolic Proteins

Abstract: Ubr1 and Ubr2 ubiquitin ligases are shown to promote degradation of misfolded cytosolic polypeptides in vivo and in a purified system in association with Hsp70.

Cited by 125 publications

References 56 publications

Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation

Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation

The Ubiquitin–Proteasome System of Saccharomyces cerevisiae

Quality Control of a Cytoplasmic Protein Complex

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