Abstract

A large proportion of the cell’s proteins must be segregated to membrane-bound organelles and multi-protein complexes. Failures in localization or assembly must be recognized by the cell and promptly degraded to avoid the accumulation of aberrant and potentially harmful proteins. Our group has taken a biochemical strategy to identify cytosolic factors that recognize mislocalized or unassembled proteins that we term orphans. We have used reconstitution approaches and experiments in mammalian cell culture to understand how they function. I will describe our ongoing efforts to identify new chaperone-like factors that identify orphan proteins and selectively target them for degradation. These factors are likely to play crucial roles in maintaining cytosolic protein homeostasis, and when mutated, may contribute to diseases of protein misfolding such as neurodegeneration. Conversely, they may be particularly crucial for facilitating rapid grow of mutation-ridden cancer cells in need to robust quality control systems.