The balance of protein expression and degradation: an ESCRTs point of view

Abstract

Endosomal sorting complexes required for transport (ESCRTs) execute the biogenesis of late endosomal multivesicular bodies (MVBs). The ESCRT pathway has traditionally been viewed as a means by which transmembrane proteins are degraded in vacuoles/lysosomes. More recent studies aimed at understanding the broader functions of ESCRTs have uncovered unexpected links with pathways that control cellular metabolism. Central to this communication is TORC1, the kinase complex that controls many of the catabolic and anabolic systems. The connection between TORC1 activity and ESCRTs allows cells to quickly adapt to the stress of nutrient limitations until the longer-term autophagic pathway is activated. Increasing evidence also points to ESCRTs regulating RNA interference (RNAi) pathways that control translation.

Figure 1

Model of the endocytic pathway of eukaryotic cells. Plasma membrane proteins are endocytosed and delivered to an early endosome from where they either recycle or continue on the way to the vacuole/lysosome. At the MVB, protein cargoes destined for degradation are packaged into ILVs. Upon fusion of the MVB with the vacuole/lyosome, the ILVs are exposed to the hydrolytic environment and both proteins and lipids are degraded. Alternatively, certain MVBs fuse with the plasma membrane and release the ILVs, termed exosomes, into the extracellular melieu. TORC1 localizes to the vacuolar membrane where it senses the amino acid content of the compartment. High amino acid levels activate TORC1 which in turn suppresses the autophagy pathway.

Figure 2

Model of the regulatory interactions between endocytosis, MVB sorting and protein translation. The active TORC1 kinase suppresses ubiquitin-dependent endocytosis of nutrient transporters and increases translation efficiency. High translation efficiency, in turn, lowers ESCRT-mediated ILV formation at the MVB (via Ist1). ILV formation at the MVB is important for the assembly of active RISC which lowers expression of specific mRNAs by inhibiting translation or inducing mRNA degradation.