Ubiquitination, quality control and degradation of membrane proteins – chance for therapies?

Abstract

Plasma membrane integrity maintenance is crucial for cell survival. Plasma membrane proteins are under tight regulation and under certain conditions are actively removed from the membrane allowing cells to adapt to changing environment. Proteins blocked in the cell membrane may interact with other molecules and form toxic aggregates. Ubiquitin is one of the most important modifiers targeting proteins for degradation and/or regulating protein functions. Several quality control mechanisms have been identified in eukaryotic cells: chaperone- dependent system that recognizes and ubiquitinates misfolded or redundant membrane proteins; protein-intrinsic LID-degron system, based on recognition of degron and ARTs-Rsp5 network that controls quality of membrane transporters. Rsp5, a Nedd4-family E3 ubiquitin ligase, is crucial for plasma membrane proteins ubiquitination. Rsp5-dependent ubiquitin action acts as a sorting signal for internalization of a membrane protein via endocytosis, recognition by the ESCRT system and vacuolar degradation. Rsp5 builds poliUb-chains on K63 and recognizes substrates through various adaptor proteins. Most of the identified Rsp5 adaptors belongs to the α-arrestin family. Plasma membrane protein ubiquitination and degradation disorders may cause neurodegenerative and cardiovascular diseases. The yeast Saccharomyces cerevisiae is one of the best models for studying trafficking pathways of membrane proteins and ubiquitination systems.