Membrane-anchored ubiquitin ligase complex is required for the turnover of lysosomal membrane proteins

Li, Ming; Koshi, Tatsuhiro; Emr, Scott D.

doi:10.1083/jcb.201505062

Cited by 57 publications

(96 citation statements)

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“…A quality control function of Tul1 at Golgi, endosomes, and the vacuole was previously shown for proteins with polar transmembrane domains. Interestingly, these proteins were not degraded via EGAD, but sorted by the ESCRT machinery for lysosomal degradation (Reggiori & Pelham, ; Valdez‐Taubas & Pelham, ; Dobzinski et al , ; Li et al , 2015a) (Fig G). Hence, substrate ubiquitination by the Dsc complex alone does not decide which proteins become ESCRT or EGAD substrates.…”

Section: Discussionmentioning

confidence: 99%

“…In budding yeast, the Dsc complex localizes to the Golgi, endosomes, and the limiting membrane of vacuoles (Reggiori & Pelham, 2002;Stewart et al, 2011;Li et al, 2015b;Yang et al, 2018), where it ubiquitinates its substrates. The Dsc substrates are thought to be exclusively degraded inside vacuoles via the ESCRT pathway (Reggiori & Pelham, 2002;Tong et al, 2014;Dobzinski et al, 2015;Li et al, 2015a;Yang et al, 2018). It is difficult to rationalize the synthetic genetic interaction of vps4D with the Dsc complex, if the Dsc complex would only function upstream of the ESCRT machinery.…”

Section: Escrt-independent Functions Of the Dsc Complex In Membrane Pmentioning

confidence: 99%

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Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

et al. 2019

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Cellular homeostasis requires the ubiquitin‐dependent degradation of membrane proteins. This was assumed to be mediated exclusively either by endoplasmic reticulum‐associated degradation ( ERAD ) or by endosomal sorting complexes required for transport ( ESCRT )‐dependent lysosomal degradation. We identified in Saccharomyces cerevisiae an additional pathway that selectively extracts membrane proteins at Golgi and endosomes for degradation by cytosolic proteasomes. One endogenous substrate of this endosome and Golgi‐associated degradation pathway ( EGAD ) is the ER ‐resident membrane protein Orm2, a negative regulator of sphingolipid biosynthesis. Orm2 degradation is initiated by phosphorylation, which triggers its ER export. Once on Golgi and endosomes, Orm2 is poly‐ubiquitinated by the membrane‐embedded “Defective in SREBP cleavage” (Dsc) ubiquitin ligase complex. Cdc48/ VCP then extracts ubiquitinated Orm2 from membranes, which is tightly coupled to the proteasomal degradation of Orm2. Thereby, EGAD prevents the accumulation of Orm2 at the ER and in post‐ ER compartments and promotes the controlled de‐repression of sphingolipid biosynthesis. Thus, the selective degradation of membrane proteins by EGAD contributes to proteostasis and lipid homeostasis in eukaryotic cells.

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Section: Discussionmentioning

confidence: 99%

Section: Escrt-independent Functions Of the Dsc Complex In Membrane Pmentioning

confidence: 99%

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

et al. 2019

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“…To answer this question, we set out to understand how vacuole membrane composition responds to environmental stresses such as starvation, and its relationship with TORC1 inactivation. As an initial test, we monitored the levels of five vacuole membrane proteins, including Vba4 (a putative amino acid permease), Fet5 (a subunit of the putative iron transporter complex, which dimerizes with Fth1), Fth1, Vph1, and Zrt3* (a variant of the zinc exporter Zrt3, please see Li et al, 2015a for details), after yeast cells enter the stationary phase. All five vacuole membrane proteins were chromosomally tagged with the green fluorescent protein (GFP), and they properly localized to the vacuole membrane ( Fig.…”

Section: Results: Torc1 Inactivation Triggers Downregulation Of Many mentioning

confidence: 99%

“…For example, depleting lysine from the cytoplasm triggers a selective degradation of the vacuolar lysine importer Ypq1 to stop lysine from being transported from the cytoplasm into the vacuole lumen (Li et al, 2015b;Sekito et al, 2014). Similarly, a low cytoplasmic Zn 2+ level leads to the downregulation of a vacuolar Zn 2+ importer, Cot1 (Li et al, 2015a).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, a cytosolic NEDD4 family E3 ligase, Rsp5, and its vacuole membrane adapter, Ssh4, are responsible for the ubiquitination of Ypq1 (Li et al, 2015b), whereas Dsc, a multi-subunit transmembrane ubiquitin ligase complex, is required for the ubiquitination of Cot1 (Li et al, 2015a;Yang et al, 2018). After ubiquitination, vacuole membrane proteins are delivered into the lumen by the endosomal sorting complexes required for transport (ESCRT) pathway (Li et al, 2015a;Li et al, 2015b;Zhu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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TORC1 regulates vacuole membrane composition through ubiquitin- and ESCRT-dependent microautophagy

Yang

Zhang

Wen

et al. 2019

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Cellular adaptation in response to nutrient limitation requires the induction of autophagy and lysosome biogenesis for the efficient recycling of macromolecules. Here, we discovered that starvation and TORC1 inactivation not only lead to the upregulation of autophagy and vacuole proteins involved in recycling, but also result in the downregulation of many vacuole membrane proteins to supply amino acids as part of a vacuole remodeling process. Downregulation of vacuole membrane proteins is initiated by ubiquitination, which is accomplished by the coordination of multiple E3 ubiquitin ligases, including Rsp5, the Dsc complex, and a newly characterized E3 ligase, Pib1. The Dsc complex is negatively regulated by TORC1 through the Rim15-Ume6 signaling cascade. After ubiquitination, vacuole membrane proteins are sorted into the lumen for degradation by ESCRT-dependent microautophagy. Thus, our study uncovered a complex relationship between TORC1 inactivation and vacuole biogenesis.

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Identification of novel arsenic resistance genes in yeast

et al. 2022

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Arsenic is a toxic metalloid that affects human health by causing numerous diseases and by being used in the treatment of acute promyelocytic leukemia. Saccharomyces cerevisiae (budding yeast) has been extensively utilized to elucidate the molecular mechanisms underlying arsenic toxicity and resistance in eukaryotes. In this study, we applied a genomic DNA overexpression strategy to identify yeast genes that provide arsenic resistance in wild‐type and arsenic‐sensitive S. cerevisiae cells. In addition to known arsenic‐related genes, our genetic screen revealed novel genes, including PHO86, VBA3, UGP1 , and TUL1 , whose overexpression conferred resistance. To gain insights into possible resistance mechanisms, we addressed the contribution of these genes to cell growth, intracellular arsenic, and protein aggregation during arsenate exposure. Overexpression of PHO86 resulted in higher cellular arsenic levels but no additional effect on protein aggregation, indicating that these cells efficiently protect their intracellular environment. VBA3 overexpression caused resistance despite higher intracellular arsenic and protein aggregation levels. Overexpression of UGP1 led to lower intracellular arsenic and protein aggregation levels while TUL1 overexpression had no impact on intracellular arsenic or protein aggregation levels. Thus, the identified genes appear to confer arsenic resistance through distinct mechanisms but the molecular details remain to be elucidated.

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Membrane-anchored ubiquitin ligase complex is required for the turnover of lysosomal membrane proteins

Abstract: VAcUL-1 and Dsc, two different E3 ubiquitin ligase complexes coexist on the vacuole membrane to regulate different subsets of membrane proteins via the vReD pathway in response to different environmental cues.

Cited by 57 publications

References 50 publications

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

TORC1 regulates vacuole membrane composition through ubiquitin- and ESCRT-dependent microautophagy

Identification of novel arsenic resistance genes in yeast

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