Membrane Protein Quality Control Mechanisms in the Endo-Lysosome System

Protein quality control (PQC) machineries play a critical role in selective identification and removal of mistargeted, misfolded, and aberrant proteins. This task is extremely complicated due to the enormous diversity of the proteome. It also requires nuanced and careful differentiation between ‘normal’ and ‘folding intermediates’ from ‘abnormal’ and ‘misfolded’ protein states. Multiple genetic and proteomic approaches have started to delineate the molecular underpinnings of how these machineries recognize their target and how their activity is regulated. In this review, we summarize our understanding of the various E3 ubiquitin ligases and associated machinery that mediate PQC in the endo-lysosome system in yeast and humans, how they are regulated, and mechanisms of target selection, with the intent of guiding future research in this area. Ubiquitin modifications serve as a general signal for protein turnover of cytosolic as well as membrane proteins.The endo-lysosome protein quality control (PQC) system is comprised of a variety of E3 ubiquitin (Ub) ligases, adaptors, and chaperones that target unwanted endocytic membrane proteins. The ubiquitinated targets are sorted by endosomal sorting complex required for transport (ESCRT) complexes into the lumen of the lysosome for degradation.Effective endo-lysosomal PQC often involves multiple, hierarchical surveillance checkpoints along the endocytic pathway to ensure removal of unwanted proteins.Endo-lysosome PQC faces the unique challenge of recognizing degradation cues arising from substrate-induced conformational changes as well as those induced by misfolding or damage from environmental stress.The adaptors of HECT E3 Ub ligases of the Nedd4 family play an active role in regulating the activity, specificity, as well as availability of the ligase on endocytic organelle membranes. Soluble and transmembrane adaptors employ unique strategies to modulate target ubiquitination.Regulation of localization as well as activity of endo-lysosome PQC machinery components is intertwined with cellular nutrient-sensing circuits.