Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways

Ravid, Tommer; Kreft, Stefan G.; Hochstrasser, Mark

doi:10.1038/sj.emboj.7600946

Cited by 252 publications

(306 citation statements)

References 42 publications

(109 reference statements)

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“…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). Our findings on Ubr1 participation in ERAD open opportunities for future studies to elucidate the molecular interplay of ubiquitin ligases.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…To a limited extent, NCC turnover was also Doa10-dependent, as a doa10⌬hrd1⌬-deficient strain stabilized NCC ERAD to a greater degree than strains in which Hrd1 alone was ablated. Doa10 participates in the degradation of cytoplasmic (ERAD-C) substrates (59,60). The observation that the Doa10 effect was only seen after ablating Hrd1 suggests that in yeast, ERAD-M processing of NCC may overshadow its quality control by ERAD-C-dependent mechanisms.…”

Section: Discussionmentioning

confidence: 97%

The Thiazide-sensitive NaCl Cotransporter Is Targeted for Chaperone-dependent Endoplasmic Reticulum-associated Degradation

Needham

Mikoluk

Dhakarwal

et al. 2011

Journal of Biological Chemistry

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Background:The cation chloride cotransporter NCC is degraded by undefined mechanisms. Results: NCC requires specific conserved machinery for chaperone-dependent recognition, ubiquitination, and proteasomal routing. Conclusion: NCC exhibits distinct ERAD requirements, which correlate with its transmembrane topology and distinguish it from other clients. Significance: These ER quality control components process misfolded conformational intermediates of NCC and other structurally related cotransporters that are vital for human health.

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“…Plates were incubated for 2 days at 30°C. The cytosolic Ura3-CL1 fusion protein was previously shown to be degraded by the Doa10 E3 pathway (24). The accumulation of Ura3-CL1 in doa10⌬ cells allowed them to grow on medium lacking uracil (right panel).…”

Section: Vms1mentioning

confidence: 99%

The Cdc48 Protein and Its Cofactor Vms1 Are Involved in Cdc13 Protein Degradation

Baek

Cheng

Kim

et al. 2012

Journal of Biological Chemistry

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Background: Vms1 is a recently isolated Cdc48 cofactor but has few degradation targets under normal growth conditions. Results: Vms1 and Cdc48 promote Cdc13 turnover, which involves both the proteasome and autophagy. Conclusion: Our study reveals novel functions of Vms1 and autophagy. Significance: Cdc13 may be the first ubiquitylated yeast protein subject to both degradation pathways under normal growth conditions.

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Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways

Cited by 252 publications

References 42 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 Thiazide-sensitive NaCl Cotransporter Is Targeted for Chaperone-dependent Endoplasmic Reticulum-associated Degradation

The Cdc48 Protein and Its Cofactor Vms1 Are Involved in Cdc13 Protein Degradation

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