The surface expression of nutrient transporters is acutely regulated by the concentration of the nutrient they pump and the metabolic state of the cell. The presence of high nutrient concentrations causes rapid endocytosis and degradation of the corresponding transporter. This negative-feedback system ensures that cytoplasmic nutrient concentration remains in a physiological range. On the other hand, metabolic stress such as glucose or amino acid starvation also triggers rapid turnover of transporters, in this case to safe energy and recover amino acids by protein degradation. This project focuses on a regulatory system that in part determines the turnover rate of yeast transporters: eisosomes and the proton pump Pma1. The majority of proton-driven nutrient transporters localize to plasma membrane structures called eisosomes. Our data suggest that eisosomes function as storage compartments in which transporters are kept in an inactive state. The storage capacity of eisosomes seems to be regulated by the activity of Pma1, a proton pump that uses ATP to maintain the proton gradient across the plasma membrane. High Pma1 activity causes the release of proton-driven transporters from eisosomes, which in turn results in rapid turnover of these proteins. This regulatory system ensures a balance between the proton influx by transporters and proton export by Pma1. Our studies will focus on the mechanism of this eisosome regulation and how the metabolic state of the cell can modulate this system.

Public Health Relevance

The proposed project studies the control of nutrient import into cells. Regulation of nutrient import plays an important role in maintaining normal metabolic function of the cell. Improper nutrient uptake is a hallmark of pathological states such as cancer and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM123147-02
Application #
9520278
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Flicker, Paula F
Project Start
2017-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Moharir, Akshay; Gay, Lincoln; Appadurai, Daniel et al. (2018) Eisosomes are metabolically regulated storage compartments for APC-type nutrient transporters. Mol Biol Cell 29:2113-2127