The quality control of mislocalised membrane and secretory proteins (360G-Wellcome-204957_Z_16_Z)

A network of integrated pathways coordinates protein synthesis and degradation enabling our cells to offset inherent defects, including misfolding and aggregation, and maintain protein homeostasis. The extremely hydrophobic transmembrane domains and targeting signals of membrane and secretory proteins pose a particular challenge, since inefficient subcellular delivery and defective membrane translocation result in the cytosolic mislocalization of these notoriously aggregation-prone precursors. We have discovered that these mislocalized proteins (MLPs) are rapidly removed via a specialised quality control pathway that employs novel adaptors and effectors to regulate their selective proteasomal degradation. What we do not understand are the molecular details of MLP quality control, how it is coordinated with membrane protein delivery and how it is integrated into global protein homeostasis. My primary objective is to define the molecular and cellular basis of MLP quality control by addressing four key questions: 1. How do exposed hydrophobic motifs elicit protein quality control in the cytosol? 2. Client sorting: how does the MLP chaperone network support both the delivery and degradation of substrates? 3. Does the client base for this specialised quality control pathway extend beyond hydrophobic MLPs? 4. How are MLP inclusion bodies formed and what is their fate?