Scientists from UT Southwestern Medical Center report in their new study that protein complexes that play a key role in immune response look like oil droplets in the water while inside the liquid environment of cells. An article in Devdiscourse suggests that understanding their formation could lead to novel interventions for overactive or underactive immune responses.
Study lead author Dr. Zhijian "James" Chen, a Professor of Molecular Biology and Director of the Center for Inflammation Research at UTSW, said that these droplets act as microreactors that concentrate the proteins and their substrates within the cell.
Protein Complexes Assemble in Droplets Inside Immune Cells; Findings Offer New Ways to Regulate Immunity
Ubiquitin Protein Explained
Ubiquitin was first discovered in 1975 and is identified to be present in all eukaryotic cells, according to Healthline. This small, 76-amino acid, regulatory protein is responsible for directing the movement of important proteins in cells by synthesizing new proteins and destroying defective ones.
Scientists found that the said regulatory protein has remained virtually unchanged throughout evolution. Since they are found in eukaryotic cells that make up plants, fungi, and animals, they are known to attach to proteins and tag them for disposal in a process called ubiquitination. Those tagged proteins are destroyed in proteasomes.
In 2004, Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry for discovering the process they call ubiquitin-mediated degradation (proteolysis).
Ubiquitin protein has been studied because of its potential to be used as a targeted therapy to treat cancer. Scientists believe that ubiquitin could eliminate cancer cells by manipulating the proteins inside them.
The study has led to the development of three proteasome inhibitors approved by the US FDA to treat multiple myeloma blood cancer. These inhibitors are bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro).
Ubiquitin for Regulating Immunity
More than 20 years ago, Dr. Chen's lab discovered ubiquitin assembles into chains inside cells that are exposed to inflammatory molecules.
According to Science Daily, he and his colleagues showed ubiquitin play a key role in immunity and can activate the IκB complex (IKK), which has the NEMO component that triggers the NF-κB protein to move to the nucleus and turn on the immune-related genes. However, it was still a mystery how NEMO and IKK came together.
In their study, titled "Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB" published in the journal Molecular Cell, the team reported that they mixed ubiquitin and NEMO in test tubes with the TRAF6 protein that promotes ubiquitin to assemble in chains.
NEMO and the polyubiquitin chains assembled into liquid droplets like oil droplets in water as they remained separate from the liquid medium. Previous experiments have shown similar reactions when cells are exposed to IL-1β or TNFα.
IKK added to the droplets activated the protein and triggered NF-κB to move to the nucleus. Dr. Chen explained that the longer the polyubiquitin chain forms larger droplets with NEMO that trigger a stronger immune response.
To test it further, they tried using NEMO altered by mutations from a rare disease called NEMO deficiency syndrome, which severely blunts immune response against infections. They found that NEMO could not effectively form into droplets with polyubiquitin chains and prevented subsequent processes from triggering an immune response.
Therefore, the study highlighted the importance of understanding the phase separation phenomenon of this protein to develop treatments for NEMO deficiency syndrome and interventions for overactive and underactive immunity.
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