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      Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis


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          Changes in nutrient availability trigger massive rearrangements of the yeast plasma membrane proteome. This work shows that the arrestin-related protein Csr2/Art8 is regulated by glucose signaling at multiple levels, allowing control of hexose transporter ubiquitylation and endocytosis upon glucose depletion.


          Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces CSR2 transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.

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                Author and article information

                J Cell Biol
                J. Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                05 June 2017
                : 216
                : 6
                : 1811-1831
                [1 ]Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75013 Paris, France
                [2 ]Proteomics Facility, Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75013 Paris, France
                [3 ]Institute of Microbiology of the Czech Academy of Sciences, v.v.i. BIOCEV, 252 50 Vestec, Czech Republic
                [4 ]Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic
                Author notes
                Correspondence to Sébastien Léon: sebastien.leon@ 123456ijm.fr

                Q. Defenouillère and V. Albanèse contributed equally to this paper.

                Author information
                © 2017 Hovsepian et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                : 26 October 2016
                : 03 February 2017
                : 28 March 2017
                Funded by: Ministère de l’Enseignement Supérieur et de la Recherche, DOI http://dx.doi.org/10.13039/501100004792;
                Funded by: Fondation ARC pour la Recherche sur le Cancer, DOI http://dx.doi.org/10.13039/501100004097;
                Award ID: DOC20160604208
                Funded by: Fondation pour la Recherche Médicale, DOI http://dx.doi.org/10.13039/501100002915;
                Award ID: SPF20150934065
                Funded by: Fondation ARC pour la Recherche sur le Cancer, DOI http://dx.doi.org/10.13039/501100004097;
                Award ID: PJA20151203368
                Funded by: Ligue Contre le Cancer, DOI http://dx.doi.org/10.13039/501100004099;
                Award ID: RS14/75-120
                Funded by: Agence Nationale pour la Recherche, DOI http://dx.doi.org/10.13039/501100001665;
                Award ID: ANR-16-CE13-0002-01
                Funded by: Czech Ministry of Education Youth and Sports, DOI http://dx.doi.org/10.13039/501100001823;
                Award ID: LQ1604 NPU II
                Funded by: Czech Science Foundation, DOI http://dx.doi.org/10.13039/501100001824;
                Award ID: 15-08225S
                Funded by: EU COST Action
                Award ID: PROTEOSTASIS BM1307
                Research Articles

                Cell biology
                Cell biology


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