Scientists at the Crick have outlined how cells raise the alarm when acids leak out of their compartments, indicating damage or infection.

Cells need acidic compartments for digestion and recycling nutrients, and acid is pumped into these compartments by a complex assembly of proteins called the V-ATPase, also known as the ‘proton pump’. 

When cells are damaged or infected with a bacteria or virus, acid leaks out of these compartments. Cells need to be able to detect this, but researchers didn’t know how.

In research published in Molecular Cell, a multidisciplinary team of scientists at the Crick discovered that the V-ATPase proton pump sounds the alarm itself.

"We’ve now discovered that the same complex which keeps parts of the cell acidic also raises the alarm if the system breaks down".

 Rupert Beale

Using specialised techniques to shed light on the structure of the pump, the researchers identified that one protein in the complex, called V1H, brings in machinery which is usually required for autophagy – degradation of parts of the cell – but is also involved in this process.

Researchers had known that some autophagy components get activated during infections, such as influenza, but it wasn’t clear how. This new work now further highlights the critical role the V-ATPase plays in maintaining the health of the cell. Moreover, the team believe that some microbes like salmonella can evade detection by antagonising the proton pump, suggesting that targeting this pathway could be a useful avenue to explore in developing new drugs.

Working with neurobiologists at the Crick, the team also discovered that a shorter form of V1H develops in nerve cells. But this form of V1H couldn’t flag to autophagy proteins that the compartment had lost its acidity.  

Because neurons have to constantly load and release chemicals called neurotransmitters in acidic compartments of the cell, the team speculate that having this shorter form of V1H allows them to carry out their specialised function without raising alarm bells unnecessarily.

Rupert and Lewis worked with many Crick teams: the Structural Biology team, the Proteomics team, the Cellular Degradation Systems Laboratory, the Mitochondrial Neurobiology Laboratory, the Neural Circuits and Evolution Laboratory, and the Neural Circuit Bioengineering and Disease Modelling Laboratory. They also worked with John Rubinstein at the University of Toronto, who discovered the structure of mammalian V-ATPase, which was vital for this research.

Rupert Beale, senior author and group leader of the Cell Biology of Infection Laboratory, said: 

“Failing to contain acid indicates danger for the cell, and we’ve now discovered that the same complex which keeps parts of the cell acidic also raises the alarm if the system breaks down. 

“There are lots of other puzzles to solve, such as how cells regulate acidity in the first place, and how nerve cells do things differently. We’re also going to start investigating if manipulating this pathway is of therapeutic use.”

Lewis Timimi, first author and MB/PhD student in the Cell Biology of Infection Laboratory, said: 

“This work shows that the V-ATPase is not only a proton pump, but also an important sensor that allows the cell to recognise damage. By identifying the subunit of the V-ATPase responsible for this function, we were able to show how the state of the V-ATPase controls these damage responses. We found that this damage-detection role of the V-ATPase is active in lots of situations, including in viral infection and following activation of certain immune receptors.”