A molecular switch on an arrestin-like protein relays glucose signaling to transporter endocytosis

Becuwe, Michel; Vieira, Neide; Lara, David; Gomes-Rezende, Jéssica; Soares‐Cunha, Carina; Casal, Margarida; Haguenauer‐Tsapis, Rosine; Vincent, Olivier; Paiva, Sandra; Léon, Sébastien

doi:10.1083/jcb.201109113

Cited by 130 publications

(347 citation statements)

References 75 publications

(125 reference statements)

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“…As shown in ART vectors and the empty LexA-containing vector (data not shown). Our results support previous reports showing a functional interaction between Rod1 and Snf1 and show that Rog3 may also be regulated in a similar way (16,19). Moreover, they suggest that Snf1 is not a general regulator of ART family proteins and support the idea of a partitioning of the functions of Rsp5 adaptor proteins to respond to different classes of environmental changes through protein phosphorylation by specific kinases, such as those related to carbon (Snf1-Rod1/Rog3) or nitrogen (Npr1-Art1) sources (12,16).…”

Section: Resultssupporting

confidence: 82%

“…Our results support previous reports showing a functional interaction between Rod1 and Snf1 and show that Rog3 may also be regulated in a similar way (16,19). Moreover, they suggest that Snf1 is not a general regulator of ART family proteins and support the idea of a partitioning of the functions of Rsp5 adaptor proteins to respond to different classes of environmental changes through protein phosphorylation by specific kinases, such as those related to carbon (Snf1-Rod1/Rog3) or nitrogen (Npr1-Art1) sources (12,16). Based on previous data in mammals implicating a role for 14-3-3 proteins in the regulation of the Rsp5 orthologue, Nedd4.2 (20,21), we tested whether the WW domains of Rsp5 physically interact with the yeast 14-3-3 protein Bmh2.…”

Section: Resultssupporting

confidence: 82%

“…We show that the regulatory domain of Snf1 (Snf1-RD) interacts with the N-terminal half of Rod1, which contains the arrestin-like domain. Interestingly, this is also the domain of Rod1 implicated in binding the protein phosphatase regulatory subunit, Reg1 (16).…”

Section: Resultsmentioning

confidence: 99%

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Regulation of the Yeast Hxt6 Hexose Transporter by the Rod1 α-Arrestin, the Snf1 Protein Kinase, and the Bmh2 14-3-3 Protein

Llopis-Torregrosa

Ferri-Blázquez

Adam‐Artigues

et al. 2016

Journal of Biological Chemistry

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Cell viability requires adaptation to changing environmental conditions. Ubiquitin-mediated endocytosis plays a crucial role in this process, because it provides a mechanism to remove transport proteins from the membrane. Arrestin-related trafficking proteins are important regulators of the endocytic pathway in yeast, facilitating selective ubiquitylation of target proteins by the E3 ubiquitin ligase, Rsp5. Specifically, Rod1 (Art4) has been reported to regulate the endocytosis of both the Hxt1, Hxt3, and Hxt6 glucose transporters and the Jen1 lactate transporter. Also, the AMP kinase homologue, Snf1, and 14-3-3 proteins have been shown to regulate Jen1 via Rod1. Here, we further characterized the role of Rod1, Snf1, and 14-3-3 in the signal transduction route involved in the endocytic regulation of the Hxt6 high affinity glucose transporter by showing that Snf1 interacts specifically with Rod1 and Rog3 (Art7), that the interaction between the Bmh2 and several arrestin-related trafficking proteins may be modulated by carbon source, and that both the 14-3-3 protein Bmh2 and the Snf1 regulatory domain interact with the arrestin-like domain containing the N-terminal half of Rod1 (amino acids 1-395). Finally, using both co-immunoprecipitation and bimolecular fluorescence complementation, we demonstrated the interaction of Rod1 with Hxt6 and showed that the localization of the Rod1-Hxt6 complex at the plasma membrane is affected by carbon source and is reduced upon overexpression of SNF1 and BMH2.An important component of the maintenance of cellular homeostasis and stress responses is the regulation of the composition of plasma membrane proteins responsible for the uptake and extrusion of nutrients and other nonpermeable small molecules. The general mechanisms controlling this regulatory process are highly conserved among eukaryotic organisms and involve both transcriptional regulation and modulation of the balance of secretion, recycling, and degradation of individual transporter proteins in response to changes in the extracellular environment (reviewed in Ref. 1). Regulated endocytosis, one important step in this process, has been well studied in both mammals and yeast, unveiling many mechanistic similarities that establish yeast as a relevant model system.In Saccharomyces cerevisiae, plasma membrane transporters that need to be down-regulated are ubiquitylated by the Rsp5 E3 ubiquitin ligase, endocytosed, sorted into multivesicular bodies in a process requiring the ESCRT machinery, and finally are delivered to the vacuole for degradation (2-5). Transporter ubiquitylation by the HECT family Rsp5 E3 ubiquitin ligase is mediated by one or more of several adaptor proteins that confer specificity and ensure the correct regulation of targeted proteins in response to changes in the extracellular environment (reviewed in Refs. 6). At least 18 Rsp5 adaptor proteins have been described, each having specificity for a subset of transport proteins and acting in response to specific stimuli.The molecular mechanisms governing th...

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Section: Resultssupporting

confidence: 82%

Section: Resultssupporting

confidence: 82%

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Regulation of the Yeast Hxt6 Hexose Transporter by the Rod1 α-Arrestin, the Snf1 Protein Kinase, and the Bmh2 14-3-3 Protein

Llopis-Torregrosa

Ferri-Blázquez

Adam‐Artigues

et al. 2016

Journal of Biological Chemistry

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“…As a consequence of directly binding Nedd4 Ub ligases, all of the a-arrestin-family proteins also undergo ubiquitination. Interestingly, mutants of Art1 or Art4 lacking their major ubiquitinatable lysine target residues function poorly as adaptors for their Can1 and Jen1 transporter substrates suggesting that ubiquitination activates the a-arrestins to bind better to substrate proteins or to the endocytic sorting machinery Becuwe et al 2012).…”

Section: Ubiquitin-dependent Sorting In Endocytosismentioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

183

176

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When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

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“…Stimulated TORC1 inhibits Npr1 by phosphorylation (6) and targets the PP2A-type Sit4 phosphatase to the Bul proteins, which are then dephosphorylated (and monoubiquitylated) and dissociate from the 14-3-3 proteins, thus leading to Rsp5-mediated ubiquitylation of Gap1 (7). This control by internal amino acids of the Bul proteins, along with the role of Art4/ Rod1 in glucose-induced endocytosis of the Jen1 lactate permease (8) and that of Art1 in cycloheximide-induced endocytosis of the Can1 arginine permease (9), illustrates that ubiquitylation of permeases can be stimulated through direct regulation of their Rsp5 adaptors.…”

mentioning

confidence: 99%

Substrate-Induced Ubiquitylation and Endocytosis of Yeast Amino Acid Permeases

Ghaddar

Ahmad

Saliba

et al. 2014

Molecular and Cellular Biology

134

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bMany plasma membrane transporters are downregulated by ubiquitylation, endocytosis, and delivery to the lysosome in response to various stimuli. We report here that two amino acid transporters of Saccharomyces cerevisiae, the general amino acid permease (Gap1) and the arginine-specific permease (Can1), undergo ubiquitin-dependent downregulation in response to their substrates and that this downregulation is not due to intracellular accumulation of the transported amino acids but to transport catalysis itself. Following an approach based on permease structural modeling, mutagenesis, and kinetic parameter analysis, we obtained evidence that substrate-induced endocytosis requires transition of the permease to a conformational state preceding substrate release into the cell. Furthermore, this transient conformation must be stable enough, and thus sufficiently populated, for the permease to undergo efficient downregulation. Additional observations, including the constitutive downregulation of two active Gap1 mutants altered in cytosolic regions, support the model that the substrate-induced conformational transition inducing endocytosis involves remodeling of cytosolic regions of the permeases, thereby promoting their recognition by arrestin-like adaptors of the Rsp5 ubiquitin ligase. Similar mechanisms might control many other plasma membrane transporters according to the external concentrations of their substrates.

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A molecular switch on an arrestin-like protein relays glucose signaling to transporter endocytosis

Abstract: Glucose remodels the post-translational modifications of the yeast arrestin-like protein Rod1 to promote glucose-induced transporter endocytosis.

Cited by 130 publications

References 75 publications

Regulation of the Yeast Hxt6 Hexose Transporter by the Rod1 α-Arrestin, the Snf1 Protein Kinase, and the Bmh2 14-3-3 Protein

Regulation of the Yeast Hxt6 Hexose Transporter by the Rod1 α-Arrestin, the Snf1 Protein Kinase, and the Bmh2 14-3-3 Protein

Ubiquitin-Dependent Sorting in Endocytosis

Substrate-Induced Ubiquitylation and Endocytosis of Yeast Amino Acid Permeases

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