scholarly journals Decision letter: Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids

2020 ◽  
Keyword(s):  
Amino Acids ◽  
Ubiquitin Ligase ◽  
Nutrient Transporter

scholarly journals Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Vasyl Ivashov ◽  
Johannes Zimmer ◽  
Sinead Schwabl ◽  
Jennifer Kahlhofer ◽  
Sabine Weys ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Amino Acid Transporters ◽  
General Amino Acid Control ◽  
Amino Acid Availability ◽  
Genome Wide ◽  
A Genome ◽  
Lysine Residues ◽  
Nutrient Transporter

How cells adjust nutrient transport across their membranes is incompletely understood. Previously, we have shown that S. cerevisiae broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through endocytosis of sugar- and amino acid transporters (AATs) (Müller et al., 2015). A genome-wide screen now revealed that the selective endocytosis of four AATs during starvation required the α-arrestin family protein Art2/Ecm21, an adaptor for the ubiquitin ligase Rsp5, and its induction through the general amino acid control pathway. Art2 uses a basic patch to recognize C-terminal acidic sorting motifs in AATs and thereby instructs Rsp5 to ubiquitinate proximal lysine residues. When amino acids are in excess, Rsp5 instead uses TORC1-activated Art1 to detect N-terminal acidic sorting motifs within the same AATs, which initiates exclusive substrate-induced endocytosis. Thus, amino acid excess or starvation activate complementary α-arrestin-Rsp5-complexes to control selective endocytosis and adapt nutrient acquisition.

scholarly journals Author response: Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids

2020 ◽  
Author(s):  
Vasyl Ivashov ◽  
Johannes Zimmer ◽  
Sinead Schwabl ◽  
Jennifer Kahlhofer ◽  
Sabine Weys ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ubiquitin Ligase ◽  
Author Response ◽  
Nutrient Transporter

scholarly journals Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway

Science ◽  
2018 ◽  
Vol 362 (6418) ◽  
pp. eaat0174 ◽  
Author(s):  
Jeong-Mok Kim ◽  
Ok-Hee Seok ◽  
Shinyeong Ju ◽  
Ji-Eun Heo ◽  
Jeonghun Yeom ◽  
...  
Keyword(s):  
Amino Acids ◽  
Stationary Phase ◽  
Ubiquitin Ligase ◽  
Bacterial Proteins ◽  
Cytosolic Ribosomes

In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. By contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt-formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N-degrons and identified the Psh1 ubiquitin ligase as the recognition component of the eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins.

scholarly journals The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gerta Hoxhaj ◽  
Edward Caddye ◽  
Ayaz Najafov ◽  
Vanessa P Houde ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Protein Phosphatase ◽  
E3 Ubiquitin Ligase ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Intracellular Amino Acid ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

scholarly journals Multiple inputs control sulfur-containing amino acid synthesis inSaccharomyces cerevisiae

2014 ◽  
Vol 25 (10) ◽  
pp. 1653-1665 ◽  
Author(s):  
Meru J. Sadhu ◽  
James J. Moresco ◽  
Anjali D. Zimmer ◽  
John R. Yates ◽  
Jasper Rine
Keyword(s):  
Amino Acids ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Acid Synthesis ◽  
Phospholipid Synthesis ◽  
Amino Acid Synthesis ◽  
Sam Synthetase ◽  
Cysteine Synthesis ◽  
Adenosyl Methionine ◽  
Sulfur Containing

In Saccharomyces cerevisiae, transcription of the MET regulon, which encodes the proteins involved in the synthesis of the sulfur-containing amino acids methionine and cysteine, is repressed by the presence of either methionine or cysteine in the environment. This repression is accomplished by ubiquitination of the transcription factor Met4, which is carried out by the SCF(Met30) E3 ubiquitin ligase. Mutants defective in MET regulon repression reveal that loss of Cho2, which is required for the methylation of phosphatidylethanolamine to produce phosphatidylcholine, leads to induction of the MET regulon. This induction is due to reduced cysteine synthesis caused by the Cho2 defects, uncovering an important link between phospholipid synthesis and cysteine synthesis. Antimorphic mutants in S-adenosyl-methionine (SAM) synthetase genes also induce the MET regulon. This effect is due, at least in part, to SAM deficiency controlling the MET regulon independently of SAM's contribution to cysteine synthesis. Finally, the Met30 protein is found in two distinct forms whose relative abundance is controlled by the availability of sulfur-containing amino acids. This modification could be involved in the nutritional control of SCF(Met30) activity toward Met4.

scholarly journals Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Céline Barthelemy ◽  
Bruno André
Keyword(s):  
Amino Acids ◽  
Plasma Membrane ◽  
Protein Kinase C ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Kinase C ◽  
Acid Transporter ◽  
Mtorc1 Activation

AbstractThe human L-type amino acid transporter 1 (LAT1), also known as SLC7A5, catalyzes the transport of large neutral amino acids across the plasma membrane. As the main transporter of several essential amino acids, notably leucine, LAT1 plays an important role in mTORC1 activation. Furthermore, it is overexpressed in various types of cancer cells, where it contributes importantly to sustained growth. Despite the importance of LAT1 in normal and tumor cells, little is known about the mechanisms that might control its activity, for example by promoting its downregulation via endocytosis. Here we report that in HeLa cells, activation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) triggers efficient endocytosis and degradation of LAT1. Under these conditions we found LAT1 downregulation to correlate with increased LAT1 ubiquitylation. This modification was considerably reduced in cells depleted of the Nedd4-2 ubiquitin ligase. By systematically mutagenizing the residues of the LAT1 cytosolic tails, we identified a group of three close lysines (K19, K25, K30) in the N-terminal tail that are important for PMA-induced ubiquitylation and downregulation. Our study thus unravels a mechanism of induced endocytosis of LAT1 elicited by Nedd4-2-mediated ubiquitylation of the transporter’s N-terminal tail.

scholarly journals Complementary α-arrestin - Rsp5 ubiquitin ligase complexes control selective nutrient transporter endocytosis in response to amino acid availability

2020 ◽  
Author(s):  
Vasyl Ivashov ◽  
Johannes Zimmer ◽  
Sinead Schwabl ◽  
Jennifer Kahlhofer ◽  
Sabine Weys ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Amino Acid Transporters ◽  
General Amino Acid Control ◽  
Amino Acid Availability ◽  
Acid Control ◽  
Genome Wide ◽  
A Genome ◽  
Lysine Residues ◽  
Nutrient Transporter

AbstractHow cells adjust transport across their membranes is incompletely understood. Previously, we have shown that S.cerevisiae broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through selective endocytosis of sugar- and amino acid transporters (AATs) (Müller et al., 2015). A genome-wide screen now revealed that Art2/Ecm21, a member of the α-arrestin family of Rsp5 ubiquitin ligase adaptors, is required for the simultaneous endocytosis of four AATs and induced during starvation by the general amino acid control pathway. Art2 uses a basic patch to recognize C-terminal acidic sorting motifs in these AATs and instructs Rsp5 to ubiquitinate proximal lysine residues. In response to amino acid excess, Rsp5 instead uses TORC1-activated Art1 to detect N-terminal acidic sorting motifs within the same AATs, which initiates exclusive substrate-induced endocytosis of individual AATs. Thus, amino acid availability activates complementary α-arrestin-Rsp5-complexes to control selective endocytosis for nutrient acquisition.

scholarly journals HerpesSimplex Virus 1 Mutant in Which the ICP0 HUL-1 E3 Ubiquitin Ligase SiteIs Disrupted Stabilizes cdc34 but Degrades D-Type Cyclins andExhibits DiminishedNeurotoxicity

2003 ◽  
Vol 77 (24) ◽  
pp. 13194-13202 ◽  
Author(s):  
Ryan Hagglund ◽  
Bernard Roizman
Keyword(s):  
Amino Acids ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Cell Protein ◽  
Ring Finger Domain ◽  
Exon 2 ◽  
Multifunctional Protein ◽  
Infected Cells

ABSTRACT Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a multifunctional protein that functions as a promiscuous transactivator and promotes the degradation of multiple cellular proteins. In vitro studies indicated that it encodes two physically separated functional E3 ubiquitin ligase domains. One, designated herpesvirus ubiquitin ligase 1 (HUL-1), maps to a region encoded by exon 3 and is contained between residues 543 and 680. Deletion of amino acids 621 to 625 abolishes this activity. The second, designated HUL-2, maps to the RING finger domain present in ICP0 encoded by exon 2. Earlier studies have shown that ICP0 stabilizes cyclins D1 and D3, and several lines of investigation led to the hypothesis that this function of ICP0 is the consequence of degradation of the E2 enzyme cdc34, known to be involved in the proteasome-dependent degradation of D-type cyclins. Consistent with this hypothesis, we have previously shown that cdc34 physically interacts with ICP0 at or near aspartate 199 and at amino acids 621 to 625 and that the former site is required for effective ubiquitylation and degradation of cdc34. Furthermore, the ICP0 HUL-1 domain promotes the polyubiquitination of cdc34 in vitro. If the mechanism by which D-type cyclins are salvaged in wild-type-infected cells is dependent on polyubiquitination and consequent destruction of cdc34, than the mutant virus R6701, which was constructed for these studies and lacks ICP0 residues 621 to 625, should destabilize the D cyclins and preclude the degradation of cdc34. We report that ICP0 residues 621 to 625 are essential for degradation of cdc34 in infected cells and for the ICP0-mediated stabilization of D-type cyclins, that a mutation that specifically disrupted the ring finger domain of the HUL-2 site had no effect on the degradation of cdc34 in infected cells, and that deletion of ICP0 residues 621 to 625 decreased the replicative capacity of the virus in growth-arrested but not in dividing cells and resulted in diminished pathogenicity on intracerebral inoculation of mice. We conclude that the ICP0 HUL-1 domain acts in infected cells to degrade cdc34 and that this function requires the interaction of cdc34 with sequences in exons 2 and 3 but does not involve the HUL-2 RING finger E3 domain.

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