Utrecht University: Research reveals how ‘chaperone’ proteins deal with immune system overreactions

The research, published in Nature Communications, provides insights into how our body keeps the immune system in check. It could also point to how special chaperone proteins can prevent the accumulation of other harmful molecules, such as those associated with Alzheimer’s disease. The research was a cooperation between scientists from Utrecht University and Imperial College London.

“We studied how specific proteins in our blood work together to kill infectious bacteria, drilling holes in their membranes,” said Prof. Albert Heck, biochemist at Utrecht University. The team studied membrane attack complexes (MACs) – components of our immune system that punch minute holes in the membrane of invading bacteria. If enough holes are punched, the bacteria will pop and die.

We studied how specific proteins in our blood work together to kill infectious bacteria, drilling holes in their membranes

Utrecht Institute for Pharmaceutical Sciences
The immune system therefore creates loads of MACs when an invader is detected. But not all of these reach their targets, meaning many end up in the bloodstream, where they could potentially damage the body’s own cells.

Scientists knew special chaperone proteins – called clusterin and vitronectin – helped to prevent these MACs from causing unwanted attacks, but didn’t know how.

Unprecedented detail
Now, the team have managed to capture and investigate in unprecedented detail MAC precursor molecules bound to the chaperone proteins, revealing how the chaperones stop MACs becoming fully functional. “Our mass spectrometry data reveal in great detail how chaperone proteins protect our own cells from off-target killing during a bacterial infection”, said Dr Marie Lukassen, from Utrecht University.

When a pathogen is detected, our immune system goes into overdrive to make MACs and not all of them reach their bacterial targets. “Here we discovered how chaperones in the blood capture rogue molecules and prevent them from damaging human cells”, said Dr Doryen Bubeck, from Imperial College London.

According to the researchers, seeing how these proteins stop MAC provides the first clues into how this branch of the immune system can be controlled. Dr Bubeck said: “This shows us how these chaperones might capture other harmful proteins in the blood”

From their detailed investigation, the team showed that clusterin attaches to a precursor version of MACs that is dissolved in the bloodstream. It then prevents the MAC from building up more of the components it needs to fully assemble and carry out its hole-punching attack.

Early precursors to Alzheimer’s disease
It’s this prevention of build-up of further material that the researchers say could provide interesting insights into other material accumulations. For example, beta-amyloid fibres, if they are allowed to accumulate, can lead to the plaques that characterise Alzheimer’s disease.

First author Anaïs Menny, from Imperial College London, said: “If clusterin uses the same method to recognise and prevent beta-amyloid accumulation as it does for MACs, then we could get some really interesting insights into how the early precursors to Alzheimer’s disease arise.”

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