Dissecting Quality Control Mechanisms of Mislocalized Proteins

Projektinformationen

MisloQC

ID Finanzhilfevereinbarung: 759427

DOI

10.3030/759427

Projekt abgeschlossen

EK-Unterschriftsdatum 20 Oktober 2017

Startdatum 1 März 2018

Enddatum 28 Februar 2023

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 497 750,00

EU-Beitrag

€ 1 497 750,00

Koordiniert durch

INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Germany

Periodic Reporting for period 4 - MisloQC (Dissecting Quality Control Mechanisms of Mislocalized Proteins)

Berichtszeitraum: 2022-09-01 bis 2023-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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.

Screenshot of project's website