| Description |
Metabolic homeostasis in eukaryotic cells is maintained largely through balancing protein synthesis and protein turnover/degradation. The multivesicular body (MVB) trafficking pathway constitutes a critical component in maintaining this balance. The MVB pathway sorts and delivers integral- and transmembrane protein cargoes from the plasma membrane of the cell to the lysosome/vacuole for degradation. The utility of this process is twofold: it modulates protein composition of the plasma membrane and, additionally, generates free amino acids which are transported to the cytosol via lysosomal/vacuolar pumps for reuse in protein synthesis. This macromolecular recycling is of particular importance during times of cellular stress or starvation. Sorting of cargoes for trafficking by the MVB pathway is performed by several multimeric protein complexes collectively termed ESCRTs (Endosomal Sorting Complex Required for Transport). These complexes assemble into a large protein network at the endosomal membrane, where they concentrate and sequester proteins for internalization into the lumen of the maturing endosomal compartment. The AAAATPase Vps4 mediates the terminal steps of MVB sorting, including the solubilization of endosomally-bound ESCRT components and the subsequent formation of the namesake multivesicular bodies via inward vesiculation of the endosomal membrane. Consequently, Vps4 plays a decisive role in the throughput of the pathway as a whole, and its activity is influenced by several regulatory factors. One such factor is the MVB-associated protein Ist1, which impacts Vps4 activity differentially according to its protein levels in the cell. Biochemical and in vivo studies in Saccharomyces cerevisiae have shown that high levels of Ist1 impede proper Vps4 recruitment, oligomerization, and ATP hydrolysis at endosomes. Conversely, low levels of Ist1 seem to promote Vps4 recruitment and activity at the endosome. Importantly, Ist1 is inherently unstable, and its expression levels vary widely throughout a normal yeast growth curve, essentially mirroring the cells' translational output: Ist1 levels peak during exponential growth and fall to nearly undetectable levels in stationary phase/starving cells. This variance, and thus the regulatory impact of Ist1, is effectuated by cellular nutrient sensing systems and starvation response pathways. These data position Ist1 as an important regulator of metabolic homeostasis, providing a link between protein synthesis and protein degradation via the MVB pathway. |
