Our immune system protects us against microbial pathogens that invade our cells and cause illness. When receptors on the cell surface detect microbes, a cascade of signals and activities within the cell is triggered, resulting in inflammation, which is part of our early defense against pathogens.
Immunologists from the RIKEN Research Center for Allergy and Immunology, Yokohama, and the Harvard School of Public Health, US, recently published a study on the regulation of this system1. Without regulation, an unstoppable immune reaction leads to excessive inflammation, which causes conditions such as asthma and arthritis.
The researchers studied a molecule called NF-κB that contains two different subunits known as p65 and p50 and normally resides in the cytoplasm of cells. When this molecule receives the appropriate signal, it enters the cell nucleus and switches on immunoregulatory genes that encode pro-inflammatory molecules. If the process is not stopped, the immune reaction continues. To terminate this reaction promptly, it is important that the p65 molecule that starts this sequence of events is degraded once it has done its job.
RIKEN’s Tsuneyasu Kaisho and his team have identified a pathway that leads to the degradation of p65. Their work shows that the process involves the specific attachment of the protein molecule ubiquitin to p65 followed by transportation of the ‘ubiquitinated’ p65 to distinct sub-nuclear domains, called nuclear bodies, where it is ultimately degraded by the proteins found there (Fig. 1).
Critically, the researchers have described a factor called PDLIM2 that has two highly important roles in the regulation of the immune response. It helps ubiquitin to bind to p65 and then targets this complex to the appropriate nuclear bodies for degradation.
The team showed that PDLIM2-deficient mouse cells had uncontrolled immune responses due to the constant activity of NF-κB and augmented production of molecules that cause inflammation. In vivo studies showed mice lacking PDLIM2 were more sensitive to stimulation of the immune response than mice with normal levels of the molecule.
Developing treatments for inflammatory and autoimmune diseases by modifying the PDLIM2-mediated pathways to terminate NF-κB p65 activation is the future aim of the team. According to team member, Takashi Tanaka, the next step towards this goal is to clarify how PDLIM2 activity itself is regulated. This is very important for developing a way to modify its activity in living cells, he says.
Reference
1. Tanaka, T., Grusby, M.J. & Kaisho, T. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nature Immunology 8, 584–591 (2007).
