Lysosomal Degradation of ER Client Proteins by ER-phagy and Related Pathways
Carla Salomo-Coll, Natalia Jiménez-Moreno, Simon Wilkinson
Abstract
• Lysosomal degradation of aberrant ER protein clients maintains cellular proteostasis. • Several pathways facilitate degradation, predominantly ER-phagy and related pathways, collectively termed ERLAD. • Clients are selected by interactions with receptors, either directly or indirectly, often in a chaperone-dependent manner. • A number of disease phenotypes are underpinned by aberrant functioning of ERLAD pathways. The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation of overabundant, misfolded, aggregating or unwanted proteins is required to maintain proteostasis and avoid the deleterious consequences of aberrant protein accumulation, at a cellular and organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it is becoming clear that there is a substantial role for lysosomal degradation of “client” proteins from the ER lumen or membrane (ER-to-lysosome degradation, ERLAD). Here we provide a brief overview of the broad categories of ERLAD – predominantly ER-phagy (ER autophagy) pathways and related processes. We collate the client proteins known to date, either individual species or categories of proteins. Where known, we summarise the molecular mechanisms by which they are selected for degradation, and the setting in which lysosomal degradation of the client(s) is important for correct cell or tissue function. Finally, we highlight the questions that remain open in this area.