Endosome and Golgi‐associated degradation (
            <scp>EGAD</scp>
            ) of membrane proteins regulates sphingolipid metabolism

Schmidt, Oliver; Weyer, Yannick; Baumann, Verena; Widerin, Michael A.; Eising, Sebastian; Angelova, Mihaela; Schleiffer, Alexander; Kremser, Leopold; Lindner, Herbert; Peter, Matthias; Fröhlich, Florian; Teis, David

doi:10.15252/embj.2018101433

Cited by 86 publications

(145 citation statements)

References 114 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…In addition, this model could also be an explanation of the different behavior of Orm1 and Orm2. While Orm2 appears to be a target of the EGAD pathway and is mainly regulated by Ypk1, Orm1 seems to be mainly regulated via the Npr1 kinase, via the TOR complex 1 signaling pathway [9,31]. However, data obtained from our metabolic flux analysis suggest that external serine is the main source for SP biosynthesis.…”

Section: Plos Geneticsmentioning

confidence: 77%

“…Cha1 is under strong transcriptional control of the Cha4 transcription factor and is known to be upregulated by exogenous serine [19]. Another protein that is slightly but significantly downregulated (p value = 0.0078, normalized ratio = 0.78) is the negative regulator of the serine palmitoyl-transferase Orm2 [7,31]. In addition, several genes involved in ergosterol biosynthesis were significantly downregulated (Erg11, Erg24, Hmg1, Erg1, Are2, Erg26).…”

Section: Plos Geneticsmentioning

confidence: 99%

See 1 more Smart Citation

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

et al. 2020

Self Cite

View full text Add to dashboard Cite

Sphingolipids are abundant and essential molecules in eukaryotes that have crucial functions as signaling molecules and as membrane components. Sphingolipid biosynthesis starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in maintaining sphingolipid homeostasis has not been precisely studied. Here we show that serine uptake is an important factor for the regulation of sphingolipid biosynthesis in Saccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino acid permease Gnp1 to be important for serine uptake. We confirm these results with serine uptake assays in gnp1Δ cells. We further show that uptake of exogenous serine by Gnp1 is important to maintain cellular serine levels and observe a specific connection between serine uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux analysis, we further observed imported serine as the main source for de novo sphingolipid biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point to analyze the role of serine uptake in mammalian sphingolipid metabolism.

show abstract

Section: Plos Geneticsmentioning

confidence: 77%

Section: Plos Geneticsmentioning

confidence: 99%

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In yeast, misfolded or damaged proteins at the Golgi were shown to undergo ubiquitination by the DSC/Tul1 E3 ligase complex, which targets them to vacuolar degradation 70,75,76 . Interestingly, while this manuscript was under review, a role for the DSC complex in targeting membranal Golgi and endosome proteins to degradation by cytosolic proteasomes was described in S. Cerevisiea 77 . Collectively, these recent findings, together with our data, define a proteasome-dependent post-ER checkpoint in the secretory pathway.…”

Section: Discussionmentioning

confidence: 99%

Golgi organization is regulated by proteasomal degradation

et al. 2020

View full text Add to dashboard Cite

The Golgi is a dynamic organelle whose correct assembly is crucial for cellular homeostasis. Perturbations in Golgi structure are associated with numerous disorders from neurodegeneration to cancer. However, whether and how dispersal of the Golgi apparatus is actively regulated under stress, and the consequences of Golgi dispersal, remain unknown. Here we demonstrate that 26S proteasomes are associated with the cytosolic surface of Golgi membranes to facilitate Golgi Apparatus-Related Degradation (GARD) and degradation of GM130 in response to Golgi stress. The degradation of GM130 is dependent on p97/VCP and 26S proteasomes, and required for Golgi dispersal. Finally, we show that perturbation of Golgi homeostasis induces cell death of multiple myeloma in vitro and in vivo, offering a therapeutic strategy for this malignancy. Taken together, this work reveals a mechanism of Golgi-localized proteasomal degradation, providing a functional link between proteostasis control and Golgi architecture, which may be critical in various secretion-related pathologies.

show abstract

“…Besides the ESCRT machinery, the endosome and Golgi-associated degradation (EGAD) pathway operates on a different set of membrane proteins that are exported from the ER. EGAD substrates are ubiquitinated on Golgi and endosomes and then extracted from membranes for proteasomal degradation (6). Ubiquitination is mediated by the defective in sterol-responsive element binding protein cleavage (Dsc) complex, a multisubunit transmembrane ubiquitin ligase reminiscent of the ERAD complexes, and extraction is executed by Cdc48 (6,7).…”

mentioning

confidence: 99%

TOR complex 2 (TORC2) signaling and the ESCRT machinery cooperate in the protection of plasma membrane integrity in yeast

Schmidt

Weyer

Sprenger

et al. 2020

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The endosomal sorting complexes required for transport (ESCRT) mediate evolutionarily conserved membrane remodeling processes. Here, we used budding yeast (Saccharomyces cerevisiae) to explore how the ESCRT machinery contributes to plasma membrane (PM) homeostasis. We found that in response to reduced membrane tension and inhibition of TOR complex 2 (TORC2), ESCRT-III/Vps4 assemblies form at the PM and help maintain membrane integrity. In turn, the growth of ESCRT mutants strongly depended on TORC2-mediated homeostatic regulation of sphingolipid (SL) metabolism. This was caused by calcineurin-dependent dephosphorylation of Orm2, a repressor of SL biosynthesis. Calcineurin activity impaired Orm2 export from the endoplasmic reticulum (ER) and thereby hampered its subsequent endosome and Golgi-associated degradation (EGAD). The ensuing accumulation of Orm2 at the ER in ESCRT mutants necessitated TORC2 signaling through its downstream kinase Ypk1, which repressed Orm2 and prevented a detrimental imbalance of SL metabolism. Our findings reveal compensatory cross-talk between the ESCRT machinery, calcineurin/TORC2 signaling, and the EGAD pathway important for the regulation of SL biosynthesis and the maintenance of PM homeostasis.

show abstract

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

Cited by 86 publications

References 114 publications

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae

Golgi organization is regulated by proteasomal degradation

TOR complex 2 (TORC2) signaling and the ESCRT machinery cooperate in the protection of plasma membrane integrity in yeast

Contact Info

Product

Resources

About