Cells expressing BCL10 fused to the fluorescent protein mScarlet, shown in pink. Image credit: Alejandro Rodríguez Gama (CC BY 4.0)
The innate immune system is the body’s first line of defence against pathogens. Although innate immune cells do not recognize specific disease-causing agents, they can detect extremely low levels of harmful organisms or substances. In response, they activate signals that lead to inflammation, which tells other cells that there is an infection. Innate immune cells are turned on in a switch-like fashion, becoming active very quickly after interacting with a pathogen. This is due to the action of signalosomes, large complexes made up of several proteins that clump together to form long chains that activate the cell.
But how do these large protein complexes assemble quick enough to create the switch-like activation observed in innate immune cells? To answer this question, Rodríguez Gama et al. focused on the CBM signalosome, which is involved in triggering inflammation through the activation of a protein called NF-kB.
First, Rodríguez Gama et al. used genetic tools to determine that activating the CBM signalosome drives a switch-like activation of NF-kB in cells. This means that individual cells in a population either become fully activated or not at all in response to minute amounts of harmful substances.
Once they had established this, Rodríguez Gama et al. wanted to know which protein in the CBM signalosome was responsible for the switch. They found that one of the proteins in the signalosome, called BCL10, has a ‘nucleation barrier’ encoded in its sequence. This means that it is very hard for BCL10 to start clumping together, but once it does, the clumps grow on their own. The nucleation barrier describes exactly how hard it is for these clumps to get started, and is determined by how disorganized the protein is.
When a pathogen ‘stimulates’ an immune cell, a tiny template is formed that lowers the nucleation barrier so that BCL10 can then aggregate itself together, leading to the switch-like behaviour observed. The nucleation barrier allows there to be more than enough BCL10 present in the cell at all times – ready to clump together at a moment’s notice – and this permits the cell to detect very low levels of a pathogen.
Rodríguez Gama et al. then tested whether BCL10 from other animals also has a nucleation barrier. They found that this feature is conserved from cnidarians, such as corals or jellyfish, to mammals, including humans. This suggests that the use of nucleation barriers to regulate innate immune signalling has existed for a long time throughout evolution.
The work by Rodríguez Gama et al. broadens our understanding of how the innate immune system senses and responds to extremely low levels of pathogens. That BCL10 is always ready to clump together suggests it may be a driving force for chronic and age-associated inflammation. Additionally, the findings of Rodríguez Gama et al. also offer insights into how other signalosomes may become activated, and offer the possibility of new drugs aimed at modifying nucleation barriers.
