A specialized “cookbook” for cancer survival
The proteasome is a protein complex organized into an empty barrel-shaped tube made up of specialized protein-degrading enzymes. This core can interact with additional cap-like subunits that govern which proteins can access the barrel for processing and the pace at which they are degraded. Different types of proteasomes are mainly classified based on the specific enzymes within the barrel, and they specialize in different types of degradation. For example, the immunoproteasome excels at producing peptides ideally suited to becoming antigens.
When the researchers started rummaging through the waste-processing machinery in tissues removed from patients with lung cancer, they noted an astonishingly large number of proteasomes that contained the protein PSME4. This protein, known as one of the regulatory “caps” making up the proteasome, was rarely found in proteasomes from adjacent, noncancerous tissues.
The team then set out to characterize the unique degradation style of the PSME4-enriched proteasomes. To illustrate what they found, imagine different proteasomes as chefs with different seasoning preferences. Some might prefer a sour flavor, while the immunoproteasome devises “sweeter” peptides that are particularly attractive to immune cells. Using advanced biochemical techniques, the team discovered that higher levels of PSME4 lead to increased production of the sour peptides in a cell and a lower amount of sweet-flavored peptides. In a series of tests, the team showed that this imbalanced ratio between sweet and sour peptides hinders the ability of the immune system to accurately identify cancer, resulting in a compromised immune response.
Based on this observation, the team hypothesized that high levels of PSME4 in a tumor could weaken patient response to immunotherapy, a treatment aimed at enabling the immune system to better combat cancer.