When a cell in the body is infected with a virus or bacterium, it 'rats out' the pathogen by putting small pieces of this pathogen's proteins on its outer surface. This enables the 'sanitary services' to identify and destroy the sick cell. Researchers from Utrecht University and other institutions shed a new light on the production of these protein pieces, which could further advance research into vaccines and cancer immunotherapies. The results were published earlier this week in the magazine Science.
Proteins can be pictured like long chains of amino acids that are strung together. A body cell produces these proteins and gets rid of them when they are no longer needed or damaged. An infected cell also produces protein chains that belong to the virus or bacterium it hosts. And a tumour cell produces mutated protein chains. When these protein chains are broken down, they are cut into pieces by a machinery called the proteasome: the resulting pieces are called peptides. The cell presents these on its outer surface, so the immune system can recognize it as 'malfunctioning'. In 2014, a Dutch research team went public with the better method they developed to measure thousands of these peptides at the same time.
Cut and stitch
In order to predict which specific peptides the cell presents, researchers use the pathogen's genetic material. The new research project shows that when proteins are broken down, the chains are not just cut up. The proteasome can also stitch pieces together forming completely new combinations. “In our Science publication, we show that we could trace only 70 % of the presented peptides back to the original genetic material,” says Professor of Biomolecular Mass Spectrometry and Proteomics Albert Heck, who was one of the researchers. "We couldn't recognize 30 % at first, but we can now with our improved measuring method. Suppose you take the alphabet as a synonym for the genome. You'll expect pieces such as ABCDE, KLMNOP or QRSTUV, but we also often found SRQP-KLM or QR-ABC, for instance.
These differently-arranged peptides could possibly be new leads for vaccines and cancer immunotherapies. The latter is in high demand all over the world right now.
‘A large fraction of HLA class I ligands are proteasome-generated spliced peptides’, Science, 21 Oct 2016 : 354-358.
This research closely fits into the Utrecht University Strategic Research Theme Life Sciences, under the sub themes Cancer and Science for Life.