Regulation of Membrane Protein Degradation by Starvation‐Response Pathways

Abstract

The multivesicular body (MVB) pathway delivers membrane proteins to the lumen of the vacuole/lysosome for degradation. The resulting amino acids are transported to the cytoplasm for reuse in protein synthesis. Our study shows that this amino acid recycling system plays an essential role in the adaptation of cells to starvation. Cells respond to amino acid starvation by up-regulating both endocytosis and the MVB pathway, thereby providing amino acids through increased protein turnover. Our data suggest that increased Rsp5-dependent ubiquitination of membrane proteins and a drop in Ist1 levels, a negative regulator of ESCRT activity, cause this response. Furthermore, we found that TORC1 and a second, unknown nutrient-sensing system are responsible for the starvation-induced protein turnover. Together, the data indicate that protein synthesis and turnover are linked by a common regulatory system that ensures adaptation and survival under nutrient-stress conditions.

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

“…Three of the 23 proteins we identified (Did2, Vps24, and Vps60) are involved in endosomal sorting and endosome-to-vacuole transport via the multivesicular body (MVB) pathway. It is known that the MVB pathway is strongly linked to the regulation of cellular metabolism, and mutants of ESCRT complexes exhibit decreased TOR activity (31,38). Interestingly, chemical-genetic profiling in yeast revealed that DID2 and VPS60 deletion mutants show strong sensitivity to rapamycin treatment (39), adding to the evidence that these genes positively influence TOR activity.…”

“…Snf7 is a core component of the ESCRT-III complex, suggesting that reduced but not abolished activity of the ESCRT-III complex extends lifespan. To our knowledge, our study represents the first time that genes involved in endosomal sorting/endosome-to-vacuole transport have been implicated in lifespan regulation, although it was known previously that ESCRT complexes are tightly linked to metabolic regulation and target of rapamycin (TOR) activity (31).…”

Glucose Starvation Inhibits Autophagy via Vacuolar Hydrolysis and Induces Plasma Membrane Internalization by Down-regulating Recycling

“…Amino Acid Analysis-Amino acid analysis was performed on cells grown to log phase or on cells grown to log phase, then washed three times into appropriate starvation media and grown for an additional 24 h. Amino acid extraction and analysis were performed as described previously (8).…”

“…This pathway promotes cell survival during amino acid starvation (8). Furthermore, in response to acute glucose starvation, proteins involved in endosomal sorting become cytosolic.…”

TRAPPIII is responsible for the vesicular transport from early endosomes to the Golgi apparatus that facilitates Atg9 cycling in autophagy

“…Scale bars: 5 mm. endosome pathway is enhanced by starvation, possibly due to the need for increased degradation in the vacuole (Hamasaki et al, 2005;Jones et al, 2012). As a result, some Atg9 in early endosomes will be relocated to late endosomes, and the late endosome-to-Golgi pathway becomes another reservoir of Atg9.…”