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HEIndividual fellowship2022–2024

ProAPP · PROTAC-driven Protein degradation by Proteasome during Antigen Processing and Presentation (ProAPP)

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2022-08-01 → 2024-10-31
EU contribution
€189,687
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

PROTAC-driven Protein degradation by Proteasome during Antigen Processing and Presentation (ProAPP)

PROteolysis TArgeting Chimeras (PROTACs) are a new type of drug that can target and destroy specific proteins in the body that are involved in diseases. They work by tagging unwanted proteins for destruction by the cell's waste disposal system, known as the ubiquitin-proteasome system. The waste disposal system also plays a role in the immune system. It helps create a set of peptides, which are small pieces of proteins that the immune system uses to recognize and fight infections/cancer. However, it is still unclear what would happen when increasing the activity of the waste disposal system can have on the immune system. This could have both good and bad effects on the immune system, like improving immunity or causing autoimmune diseases, where the body attacks itself. The drugs might change the balance of peptides, which could affect the immune system. The goal of the research is to understand how these drugs impact the balance of proteins and peptides in the cell and how they might affect the immune system. The research focuses on a specific protein called KRas, which is often altered in cancer. Understanding how PROTACs affect this protein could help us learn more about their potential as cancer treatments.

Data: CORDIS, © European Union

Project objective

PROteolysis TArgeting Chimera (PROTAC) is a new and attractive therapeutic approach that regulates a target protein by channeling it to the proteasome for degradation (an energy-demanding pathway). Concurrently, proteasomes also play a central role in generating the peptide repertoire for antigen presentation on the Human Leukocyte Antigen-I (HLA-I) molecules. A few years after PROTAC was invented, proteasomes were found to catalyze not only canonical peptide bond hydrolysis, but are also capable of “cut-and-paste” events, i.e. generating spliced peptides, which have been shown to be frequently presented n HLA-I immunopeptidomes. It is unclear how PROTAC-driven proteasome degradation modulates the spliced and non-spliced peptide repertoire derived from a targeted protein. Alterations in peptide variety and quantity produced by proteasome may lead to strong implications on the HLA-I immunopeptidome, and, hence, could result in immune implications. Therefore, using the key oncoprotein KRAS as a PROTAC’s target, this study intends to understand: (i) how PROTAC-driven KRAS degradation affects cellular pathways on a system-wide level; (ii) the impact of PROTAC on KRAS derived peptide repertoire generated by proteasomes; (iii) to what extent PROTAC enhances KRAS derived peptide presentation on HLA-I molecules. Through the combination of a multidisciplinary approach; molecular biology, biochemistry, proteomics, bioinformatics and cellular immunology, this study will provide a better fundamental understanding of the effect of PROTAC-KRAS on the cellular proteome, proteasome-derived peptide repertoire (spliced and non-spliced peptides) and HLA-I immunopeptidome landscape, thus, provide insights into the suitability of PROTAC-KRAS application as a therapeutic approach for anti-cancer therapies. Additionally, this project will deepen our understanding of the role of spliced peptides in the antigen processing and presentation pathway.

Original text from CORDIS.

Participants

  • MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany

Links

Data: CORDIS, © European Union