Saccharomyces cerivisiae as a model system for kidney disease: what can yeast tell us about renal function?

Kolb, Alexander; Buck, Teresa M.; Brodsky, Jeffrey L.

doi:10.1152/ajprenal.00141.2011

Cited by 15 publications

(15 citation statements)

References 140 publications

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“…These data are in line with numerous reports that a significant fraction of wild-type (WT), polytopic membrane proteins fold inefficiently and are subject to ERAD [36]. Alternatively, ER-associated quality control may provide a means (along with endocytosis) to regulate ENaC levels [37,38]. Indeed, a growing number of substrates in both yeast and mammals are proteins whose steady-state levels are regulated by ERAD [39–43].…”

Section: Introductionsupporting

confidence: 84%

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

Buck

Jordahl

Yates

et al. 2017

Biochemical Journal

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In the kidney, the epithelial sodium channel (ENaC) regulates blood pressure through control of sodium and volume homeostasis, and in the lung, ENaC regulates the volume of airway and alveolar fluids. ENaC is a heterotrimer of homologous α-, β- and γ-subunits, and assembles in the endoplasmic reticulum (ER) before it traffics to and functions at the plasma membrane. Improperly folded or orphaned ENaC subunits are subject to ER quality control and targeted for ER-associated degradation (ERAD). We previously established that a conserved, ER lumenal, molecular chaperone, Lhs1/GRP170, selects αENaC, but not β- or γ-ENaC, for degradation when the ENaC subunits were individually expressed. We now find that when all three subunits are co-expressed, Lhs1-facilitated ERAD was blocked. To determine which domain–domain interactions between the ENaC subunits are critical for chaperone-dependent quality control, we employed a yeast model and expressed chimeric α/βENaC constructs in the context of the ENaC heterotrimer. We discovered that the βENaC transmembrane domain was sufficient to prevent the Lhs1-dependent degradation of the α-subunit in the context of the ENaC heterotrimer. Our work also found that Lhs1 delivers αENaC for proteasome-mediated degradation after the protein has become polyubiquitinated. These data indicate that the Lhs1 chaperone selectively recognizes an immature form of αENaC, one which has failed to correctly assemble with the other channel subunits via its transmembrane domain.

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Section: Introductionsupporting

confidence: 84%

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

Buck

Jordahl

Yates

et al. 2017

Biochemical Journal

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“…Based on this finding, we reasoned that cytoplasmic Hsp70 may not simply act as a holding factor that promotes NCC ER retention in MDCK cells but that it may also interact in a protein complex with NCC to promote its degradation. Indeed, 35 S metabolic labeling and pulse-chase studies in MDCK cells confirmed that Hsp70 overexpression accelerated the rate of NCC degradation by ϳ50% (Fig. 6B).…”

Section: Ssa1 Function Contributes To Ncc Ubiquitination In Yeast-mentioning

confidence: 70%

“…The yeast system can then be exploited to identify the unique degradation requirements for each substrate by examining the protein fate in cells mutated for specific genes, such as those required for ERAD (35). These include both cytosolic and ER luminal chaperones, E3 ubiquitin ligases, and components required to retrotranslocate substrates from the ER to the cytoplasm for delivery to the proteasome.…”

Section: Ncc Can Be Expressed In the Yeast S Cerevisiae And Residesmentioning

confidence: 99%

“…S6). Cells were pulse-labeled with 35 S, and anti-HA-NCC immunoprecipitates were subjected to treatment with the N-glycosidases endoglycosidase H (which selectively cleaves high mannose core N-glycans), or peptide N-glycosidase F, which cleaves both mature and core N-glycans). As predicted, the 110-kDa band shifted slightly in response to treatment with both enzymes, confirming that this band corresponds to core NCC (supplemental Fig.…”

Section: Ssa1 Function Contributes To Ncc Ubiquitination In Yeast-mentioning

confidence: 99%

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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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“…In summary, our results clearly showed that S . cerevisiae mutant cells lacking plasma‐membrane alkali–metal cation exporters and the vacuolar cation–chloride co‐transporter may serve for the characterization of the substrate specificity and transport activity of human wild‐type and mutated cation–chloride co‐transporters, and thus serve as a model system for the study of, for example, kidney disease (Kolb et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Human NKCC2 cation–Cl^– co‐transporter complements lack of Vhc1 transporter in yeast vacuolar membranes

Petrezsélyová

Domínguez

Herynkova

et al. 2013

Yeast

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Cation-chloride co-transporters serve to transport Cl -and alkali metal cations. Whereas a large family of these exists in higher eukaryotes, yeasts only possess one cation-chloride co-transporter, Vhc1, localized to the vacuolar membrane. In this study, the human cation-chloride co-transporter NKCC2 complemented the phenotype of VHC1 deletion in Saccharomyces cerevisiae and its activity controlled the growth of salt-sensitive yeast cells in the presence of high KCl, NaCl and LiCl. A S. cerevisiae mutant lacking plasma-membrane alkali-metal cation exporters Nha1 and Ena1-5 and the vacuolar cation-chloride co-transporter Vhc1 is highly sensitive to increased concentrations of alkali-metal cations, and it proved to be a suitable model for characterizing the substrate specificity and transport activity of human wild-type and mutated cation-chloride co-transporters.

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Saccharomyces cerivisiae as a model system for kidney disease: what can yeast tell us about renal function?

Cited by 15 publications

References 140 publications

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

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

Human NKCC2 cation–Cl^– co‐transporter complements lack of Vhc1 transporter in yeast vacuolar membranes

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Saccharomyces cerivisiae as a model system for kidney disease: what can yeast tell us about renal function?

Cited by 15 publications

References 140 publications

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

Interactions between intersubunit transmembrane domains regulate the chaperone-dependent degradation of an oligomeric membrane protein

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

Human NKCC2 cation–Cl– co‐transporter complements lack of Vhc1 transporter in yeast vacuolar membranes

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Human NKCC2 cation–Cl^– co‐transporter complements lack of Vhc1 transporter in yeast vacuolar membranes