Researchers have identified a previously unknown molecular switch that amplifies inflammatory cell death in humans but is absent from mice, potentially helping to explain why animal studies do not always predict human disease.
Cells are constantly receiving signals that tell them what to do. Some promote growth and repair, while others trigger a carefully controlled form of cell death known as apoptosis, which helps the body eliminate damaged, infected or potentially dangerous cells.
One of the most important molecules involved in these decisions is tumour necrosis factor (TNF), which is produced during infection and inflammation. TNF can either help cells survive or push them towards death, but exactly how cells make this choice has puzzled researchers for decades.
Now, researchers in the MacFarlane lab have contributed to a study led by the Ryan lab at the CRUK Scotland Institute and published in Molecular Cell that uncovers an unexpected mechanism that tips the balance towards cell death. The discovery reveals a previously hidden feedback system within the TNF signalling pathway and highlights an important biological difference between humans and the laboratory mice used in most biomedical research.
The research focuses on p62, a protein best known for its role in autophagy, the cell's recycling system. The team found that when TNF activates a death-inducing pathway, it switches on a proteolytic enzyme called caspase-8, which cuts p62 into a smaller fragment known as tr-p62.
Rather than being a by-product of cell death, tr-p62 actively strengthens the death signal, helping to create an amplifying signal that drives cells more rapidly towards apoptosis.
Perhaps the most surprising finding was that this mechanism appears to be unique to humans and some other species. Human p62 contains a specific molecular cutting site that allows tr-p62 to form, whereas mouse p62 lacks this site and cannot naturally activate the same amplification system.
To explore the impact of this difference, researchers engineered mouse cells and mice to carry a human-like version of p62. The modified animals became much more sensitive to inflammatory signals, showing increased susceptibility to inflammatory shock and more severe intestinal inflammation.
The findings could help explain a longstanding challenge in biomedical research. Mice are widely used to study inflammation and test potential treatments, yet therapies that show promise in mice often fail in people. If a key component of the human TNF cell-death pathway is missing in mice, existing models may not fully reflect human inflammatory disease.
The study also reveals a new link between autophagy and inflammation. When autophagy – the cell’s recycling scheme - is impaired, p62 can accumulate within cells, creating a larger pool that can be converted into the death-promoting tr-p62 fragment. Rather than simply helping with cellular recycling, p62 appears to play a direct role in regulating inflammatory cell-death signalling.
While further research is needed, the discovery provides an important new piece of the inflammation puzzle and could support the development of better disease models and future therapies for inflammatory conditions such as inflammatory bowel disease.
‘Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF’ was published in Molecular Cell. Read the full publication here.