Abstract
Nutrient starvation induces the degradation of specific plasma membrane proteins through the multivesicular body (MVB) sorting pathway and of vacuolar membrane proteins through microautophagy. Both of these processes require the gateway protein Vps27, which recognizes ubiquitinated cargo proteins at phosphatidylinositol 3-phosphate-rich membranes as part of a heterodimeric complex coined endosomal sorting complex required for transport 0. The target of rapamycin complex 1 (TORC1), a nutrient-activated central regulator of cell growth, directly phosphorylates Vps27 to antagonize its function in microautophagy, but whether this also serves to restrain MVB sorting at endosomes is still an open question. Here, we show that TORC1 inhibits both the MVB pathway-driven turnover of the plasma membrane-resident high-affinity methionine permease Mup1 and the inositol transporter Itr1 and the microautophagy-dependent degradation of the vacuolar membrane-associated v-ATPase subunit Vph1. Using a Vps277D variant that mimics the TORC1-phosphorylated state of Vps27, we further show that cargo sorting of Vph1 at the vacuolar membrane, but not of Mup1 and Itr1 at endosomes, is sensitive to the TORC1-controlled modifications of Vps27. Thus, TORC1 specifically modulates microautophagy through phosphorylation of Vps27, but controls MVB sorting through alternative mechanisms.
Highlights
Living cells control growth in a homeostatic manner by tightly coupling protein synthesis and catabolism to the availability of nutrients
Using a Vps277D variant that mimics the target of rapamycin complex 1 (TORC1)-triggered phosphorylated state of Vps27, we further show that cargo sorting during microautophagy, but not multivesicular body (MVB) sorting, is sensitive to the TORC1-controlled modifications of Vps27
The data presented here corroborate our recent discovery according to which TORC1 controls microautophagy through phosphorylation of Vps27, and indicate that the respective regulatory mechanism does not modulate the flux through the MVB pathway
Summary
Living cells control growth in a homeostatic manner by tightly coupling protein synthesis and catabolism to the availability of nutrients. Recent studies have demonstrated that ESCRT drives microautophagy at lysosomal (i.e., yeast vacuolar) membranes, ESCRT-independent subtypes of microautophagy may exist (Oku and Sakai 2018) In both processes, MVB sorting at endosomal membranes and ESCRT-driven microautophagy at vacuolar membranes, Vps forms a heterodimer with Hse (named ESCRT-0) that initiates the sorting of membrane-resident and associated proteins following their posttranslational ubiquitination. Cargo recognition by ESCRT-0 is followed by invagination of the cargo-containing membrane and formation of intraluminal vesicles that are directly degraded within the vacuole (during microautophagy) or following the fusion of endosome-derived MVBs with the vacuole (during the ultimate step of the MVB pathway) How nutrients control these processes has largely remained elusive
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