Periodic Reporting for period 4 - MisloQC (Dissecting Quality Control Mechanisms of Mislocalized Proteins)
Reporting period: 2022-09-01 to 2023-02-28
Protein quality control systems maintain a functional proteome through detection and removal of abnormal proteins. Among them are mislocalized proteins, which are proteins that either fail to reach their native subcellular 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 not well understood. In this project our goal is 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, and shed light on their roles under both normal and perturbed conditions, such as cancer and aging.
Despite the ubiquity of protein mislocalization, the systems performing quality control of mislocalized proteins are not well understood. In this project our goal is 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, and shed light on their roles under both normal and perturbed conditions, such as cancer and aging.
In ongoing work, we established a platform for protein mislocalization in budding yeast and used it to identify proteins that are targeted for degradation specifically when mislocalized. In addition, we performed a systematic characterization of the yeast ubiquitin-proteasome system (UPS), the key system of selective protein degradation in eukaryotes. These experiments yielded a rich resource to explore functions of selective protein degradation and to understand the roles of the UPS in quality control of mislocalized proteins.
This work will provide a comprehensive picture of quality control systems for mislocalized proteins. It will allow us and others to integrate data on different quality control systems (i) to understand how protein quality control is coordinated with protein synthesis, folding and trafficking, (ii) to elucidate how cells differentiate between abnormal proteins and intermediates in protein maturation, (iii) to understand how cells use post-translational mechanisms to fine-tune protein synthesis and adapt to challenges in proteome homeostasis. Finally, exploring the link between protein mislocalization and aneuploidy could provide new targets for cancer therapy development.