Systematic chopping – protein recycling for immune defense

Protein recycling for immune defense

The waste system in living cells, the proteasome, does more than just break down worn-out or damaged proteins. It also helps the immune system recognize cancer cells or cells infected with a virus by producing protein extracts called immunopeptides. In an international collaboration, researchers led by Julian Lippi at the Max Planck Institute (MPI) for Interdisciplinary Natural Sciences have recreated protein degradation by the proteasome in vitro and identified and quantified the peptides formed. The generated dataset could in the future help in the prediction of immunogenic peptides and the development of new vaccines against infectious diseases or cancer.

Circular economy and recycling – a hot topic these days. Living cells have already mastered something that does not run smoothly in our daily lives: the proteasome, as a recycling system, breaks down proteins that are no longer needed or that have been damaged. The resulting peptides can then be used as building blocks for new proteins or brought to the cell surface, where they act as “signal flags” for our immune system. Certain cells in our immune system check whether it is our own or foreign. “Based on the unknown peptides, they realized that something was wrong here!” “In this way, the immune cells can distinguish between healthy and infected or cancerous cells,” explains Julianne Libby, head of the research group at the MPI Interdisciplinary Natural Sciences. The immune system can then destroy the cells. Infected or cancerous cells.

Recycling under a microscope

But the proteasome doesn't just break proteins down into smaller peptides. It can also put many of them back together. This process is called peptide binding. A large number of peptides presented to the immune system are such spliced ​​variants.

Research group Quantitative and systems biology um Liepe is particularly interested in the question of which spliced ​​peptides contribute to immune defense and which bases are produced by the proteasome. “For example, if we know which spliced ​​cancer peptides cancer cells present to the immune system, they could potentially be used for immunotherapy in the future. To do this, we need to know what specific peptides are produced by the proteasome and what their importance is.”

In order to better understand the peptide binding process, the researchers used a laboratory experiment to simulate how the proteasome breaks down entire proteins and qualitatively and quantitatively identify the peptides produced in the process. In this comprehensive project, the research team collaborated closely with scientists from Francis Crick Institute And the King's College London (Great Britain), National University of Singapore In addition to the teams led by Stefan Becker, Ashwin Shari and Henning Urlaub at MPI. Together they have generated the largest known data set of peptides produced from proteins by the proteasome under laboratory conditions.

In addition to biochemical experiments and mass spectrometry methods, the researchers also used computer-aided methods, some of which are based on machine learning. “Among other things, we have developed new computer programs to identify and quantify unspliced ​​and cross-linked peptides,” says Libby..

Because of coincidence

Using their data, scientists discovered some of the secrets of the proteasome. Cutting or joining of peptides does not occur by chance. “We found that the proteasome preferentially processes certain protein regions,” explains Michel Michto, head of the London research group. “This is due, among other things, to the proteasome's preferences for certain sequences of protein building blocks,” says Wai Tok Soh. “We also discovered clear properties of how spliced ​​and unspliced ​​peptides differ,” adds Hannah Rutschke, who, along with Suh and John Cormican, is first author on the paper now published in the journal. Nature Communications Published work.

New methods for vaccine research

“If we know how the proteasome produces immunogenic peptides, we can predict peptide binding. These predictions could in turn support the development of new vaccines against cancer or infectious diseases in the future,” says Libby, head of the Max Planck Research Group.