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.

Faculty of Science Charles University BIOCEV 252 50 Vestec Czech Republic

Institut Jacques Monod UMR 7592 Centre National de la Recherche Scientifique Université Paris Diderot Sorbonne Paris Cité 75013 Paris France

Institute of Microbiology of the Czech Academy of Sciences v v i BIOCEV 252 50 Vestec Czech Republic

Proteomics Facility Institut Jacques Monod UMR 7592 Centre National de la Recherche Scientifique Université Paris Diderot Sorbonne Paris Cité 75013 Paris France

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The yeast 14-3-3 proteins Bmh1 and Bmh2 regulate key signaling pathways