Normal UBC13 (green) and TRAF6 (blue) bind to launch immune response (top right). Shigella comes in between and stops their binding. Image credit: Arun Geetha Surendran (CC BY 4.0)
Shigella is a highly infectious group of bacteria that attack the human digestive tract, causing severe and often deadly diarrhoea, especially in children. There is currently no vaccine to protect against the disease, and some strains are also now resistant to antibiotics. People get infected by eating or drinking contaminated foods and water. After passing through the stomach, Shigella invades and then multiplies in the lining of the intestine, eventually causing tissue damage and irritation.
During this process, Shigella ‘hides’ from its host’s immune system by blocking how intestinal cells respond to infection. Normally, infected cells send out chemical signals that act like a call for help, attracting specialised immune cells to clear the infection. In intestinal cells, two proteins called UBC13 and TRAF6 work together to switch on this response. Specifically, TRAF6 needs to bind to UBC13 for the switch to turn on.
Like many proteins, UBC13 is formed of thousands of atoms; some of these are organized in ‘functional groups’, a collection of atoms joined in a specific manner and with special chemical properties. During Shigella infection, the bacteria produce an enzyme that changes a single functional group (an amino group) at a specific location within UBC13 for a different one (an hydroxyl group).
Previous research showed that this could stop the immune response in intestinal cells, but the mechanism remained unknown. Mohanty et al. therefore set out to determine exactly how a change of so few atoms could have such a dramatic effect.
Biochemical studies using purified proteins revealed that Shigella’s alteration to UBC13 did not change its overall structure. However, the altered protein could no longer bind to its partner TRAF6. Theoretical analysis and computer simulations revealed that the normal binding process relies on a positively charged amino acid (one of the protein’s building blocks) in UBC13 and a negatively charged one in TRAF6 being attracted to each other. Shigella’s substitution, however, introduces a second negatively charged amino acid in UBC13. This ‘steals’ the positively charged amino acid that would normally interact with TRAF6: the electrical attraction between the two proteins is disrupted, and this stops them from binding.
The work by Mohanty et al. reveals the exact mechanism Shigella uses to dampen its host’s immune response during infection. In the future, this knowledge could be used to develop more effective drugs that would help control outbreaks of diarrhoea.
