Helping the immune system out
Since 2017, Juliane Liepe’s research group Quantitative and Systems Biology has been investigating how our cellular waste plant, the proteasome, supports the immune system in recognizing virus-infected and tumor cells. Close collaboration and interdisciplinarity within and beyond our institute are essential for this.
It is Thursday evening. While the institute is slowly emptying elsewhere, the seminar room of the Quantitative and Systems Biology research group is just starting to fill up. Board games lie on the table, laughter echoes through the room, and soft drinks are opened: It is the weekly games night of Juliane Liepe’s group. Whether it is chess, Dobble, or the video game Mario Kart, it does not matter – the main thing is getting together. The team has a lot of fun and commitment, not only after work but also in their research, where the topic is much more complex than a game manual.
Recycling for the immune system
Plastic, electronics, paper – in the best case, our everyday waste is recycled. Living cells also conserve their resources by recycling components no longer needed with the help of the cellular waste plant, the proteasome. This large protein complex looks like a barrel and is hollow inside. Using a molecular label called ubiquitin, comparable to a barcode, it recognizes defective or harmful proteins. The proteasome breaks these proteins down into smaller pieces, known as peptides. These can then be used as building blocks for new proteins or brought to the cell surface, where they serve as “signal flags” for our immune system. Specific cells in our immune defense system, T cells, check whether these peptides are endogenous or foreign. If, for example, the foreign peptides originate from viruses or cancer cells, the T cells can destroy the infected cells.
But the proteasome can do even more: Similar to pieces of paper put together again in a different way, it can reassemble previously cut proteins into new peptides. But why all this effort? “When a protein is divided into smaller components, there is a fixed number of peptides depending on the number of cuts. The trick with peptide splicing is that the fragments are recombined with each other, which creates new peptide variants,” Juliane Liepe says. What scientists categorized as a curiosity turned out to be more common than expected: There is a considerable proportion of spliced peptides among the peptides presented to the immune system. Various studies have shown that these take on crucial immune functions. “Although peptide splicing was first described 20 years ago, the mechanism behind it is still not fully understood,” reports postdoctoral researcher Nyet Cheng Chiam. “That is what makes our research so fascinating.”
Multidisciplinarity is key
The research group is particularly interested in which spliced peptides contribute to immune defense and how we can predict them. To find out, the team combines biochemical and bioinformatic methods. “We stimulate the degradation of certain proteins in a test tube and then investigate whether spliced peptides are generated,” says postdoctoral researcher Wai Tuck Soh, describing the experiment. To analyze the degradation products of the proteasome, the scientists rely on the equipment and expertise of Henning Urlaub’s Bioanalytical Mass Spectrometry research group, among others.
Even though some of the team members work in the lab, 90 percent of their research happens with help of computers. Liepe’s group develops special computer programs to identify and predict spliced peptides. “To detect spliced peptides in large data sets, we constantly need to develop and improvealgorithms,” describes PhD student Yehor Horokhovskyi.
The fight against cancer
Spliced peptides can, for example, contain specific mutations that indicate a cancer cell. “If we understand which peptides cancer cells present on their surface, we can help the immune system along,” explains the research group leader. Many cancer cells have developed strategies for not being attacked. For example, they have mutated the transport system of the peptides to the cell surface so that only a few peptides are presented there – the immune response is weaker. If we know the tumor peptides cancer cells present to the immune system, it may be possible to use them for immunotherapies in the future.
Once the team has discovered promising peptide candidates, these are tested on patient samples by cooperation partners in other labs and institutions. They investigate whether the corresponding peptide triggers an immune response when added to the immune cells in blood samples. One example of success is a spliced peptide candidate identified by the Liepe group with a mutation that occurs in pancreatic cancer, among others. Peptides against other types of cancer are also soon to be tested.
Inspiration through cooperation
Since 2017, Juliane Liepe has her own team at the MPI-NAT. While it started with just a few doctoral students, by 2024 it had ten members. There is also a close collaboration with the Molecular Immunology Laboratory headed by Michele Mishto at the Francis Crick Institute in London (UK). The cooperation is so close that the research groups hold their lab meetings together – one doctoral student even works in both groups and commutes regularly. The collaboration drives their research forward: “Over the last years, a lot of new ideas have emerged from this,” recalls the bioinformatician. “The more clever minds think about certain problems, the more likely it is that we will find good solutions.” (eh / cr)
