quality control of mislocalized proteins

Protein quality control systems contribute to proteome homeostasis through prevention, detection and removal of abnormal proteins. These systems operate throughout the protein life cycle, from synthesis to degradation. Hence the definition of abnormal protein is very broad, including mutated, misfolded, mislocalized and damaged molecules. Because protein quality control occurs in all cells, it is associated with a wide range of diseases, including some cancers and late-onset neurodegenerative disorders. Moreover, abnormal proteins that escape protein quality control accumulate with aging. Thus, understanding the mechanisms of protein quality control is not only important from the point of view of basic research but can also contribute to elucidating causes of diseases at the molecular level.

Here we will periodically report on our efforts to understand how cells deal with one specific type of abormal proteins - mislocalized proteins. Mislocalized proteins are defined as proteins that fail to reach their native compartment or fail to assemble into their native complex, and thus cannot function normally. Protein mislocalization is a constitutive problem caused by inefficiencies of cellular processes and increases with aging. Proteins can also mislocalize due to mutations, as seen in various metabolic, cardiovascular and neurodegenerative diseases, and some types of cancer. Despite the ubiquity of protein mislocalization, the systems performing quality control of mislocalized proteins are unknown for most of the proteome because quality control substrates are usually rare, thus difficult to identify, and there is considerable redundancy built into quality control systems. We aim to systematically dissect quality control mechanisms of mislocalized proteins through a combination of molecular biology, genetics, biochemistry and computational biology in yeast and human cells. We will establish a platform for conditional protein mislocalization and apply it to identify quality control substrates proteome-wide, to dissect redundancies in quality control systems, to identify the machinery responsible for quality control of mislocalized proteins and to map the features involved in substrate recognition by the quality control machinery. Finally, we will exploit our findings to selectively target aneuploid cancer cells, which exhibit a high burden of mislocalized proteins. This work will provide a comprehensive picture of quality control systems for mislocalized proteins and shed light on their roles under both normal and perturbed conditions.