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

Vasyl Ivashov,Günther K Bonn,Lukas A Huber,Herbert Lindner,Johannes Zimmer,Sebastien Leon,Jennifer Kahlhofer,Sinead Schwabl,Ronald Gstir,Oliver Schmidt,Sabine Weys,Leopold Kremser,Thomas Jakschitz,David Teis

doi:10.7554/elife.58246

Abstract

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.

Highlights

Cells regulate the import of amino acids, glucose, and other nutrients to fuel metabolism, sustain growth or maintain homeostasis
We find that target of rapamycin complex 1 (TORC1) signaling and the general amino acid control (GAAC) pathway toggle Art1- or Art2-Rsp5 complex activities to induce endocytosis of the same set of four different acid transporters (AATs) depending on amino acid availability
Amino acid availability induces selective endocytosis of nutrient transporters We employed S. cerevisiae as a model system to address how eukaryotic cells adjust their nutrient transporters at the plasma membrane (PM) to nutrient availability

Summary

Introduction

Cells regulate the import of amino acids, glucose, and other nutrients to fuel metabolism, sustain growth or maintain homeostasis. Mutations in AATs cause severe defects of amino acid metabolism, and the deregulation of AATs is linked to a range of human pathologies, including neurodegenerative diseases, diabetes and cancer (Kandasamy et al, 2018; Smith, 1990; McCracken and Edinger, 2013; Zhang et al, 2017). AATs belong to the family of solute carriers (SLCs) and form selective pores that change from an outward- to an inward-facing conformation and thereby transport their amino acid substrates across membranes. The addition of AATs to the PM or their selective removal by endocytosis determines quantity and quality of amino acid transport. The molecular mechanisms leading to the selective endocytosis of AATs are largely unclear

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