Regulation of nutrient transporters by metabolic and environmental stresses

Abstract

The yeast plasma membrane is a selective barrier between an erratic environment and the cell's metabolism. Nutrient transporters are the gatekeepers that control the import of molecules feeding into the metabolic pathways. Nutrient import adjusts rapidly to changes in metabolism and the environment, which is accomplished by regulating the surface expression of transporters. Recent studies indicate that the lipid environment in which transporters function regulates ubiquitination efficiency and endocytosis of these proteins. Changes in the lipid environment are caused by lateral movements of the transporters between different membrane domains and by the influence of the extracellular environment on the fluidity of the plasma membrane.

Keywords: Alpha-arrestin; Eisosome; Membrane tension; Metabolism; Nutrient transporter; TORC2.

Figure 1.

Model of APC transporter regulation (see Table 1 for descriptions of the various proteins). A) Cell surface expression of APC transporters is regulated by the metabolism of the cell. AMPK is activated by low energy levels which increases APC transporter downregulation by regulating eisosomes and ART adaptors. Furthermore, high nutrient levels (e.g. amino acids) cause APC transporter degradation by stabilizing the inward-open conformation of the corresponding transporter. Glucose transporters (MFS transporters) are not proton driven and are regulated by AMPK in opposite way compared to the APC transporters (low energy levels stabilize these transporters). B) Stress conditions such as heat-shock, hypoosmotic shock, high pH or the presence of hydrophilic compounds increase fluidity of the plasma membrane, which results in the disassembly of the eisosome membrane domain (eisosome flattening). As a result of high membrane fluidity, APC transporters are highly active (even in absence of substrate), resulting in efficient ubiquitination and degradation of these transporters. In addition, eisosome flattening activates the TORC2-mediated stress response pathway.

Figure 2.

At the cell surface, four different mechanisms are involved in the regulation of APC transporter degradation. The key regulatory step is indicated in green. It should be noted that the first 3 mechanisms are increasing activity of APC transporters (activity and turnover of APC transporters are linked).