Cells have a crystal trigger that causes them to self-destruct when viruses invade them

Cells have a crystal trigger that causes them to self-destruct when viruses invade them

By Viviane Callier edited by Tanya Lewis

The immune system has a difficult job: When a small virus invades one of our cells, that cell must detect it and, within minutes, decide what to do. If the cell self-destructs quickly, that will prevent the virus from spreading throughout the body. But such a response to a false alarm will mean that the cell will die unnecessarily.

Now researchers have discovered that a special group of about 100 immune proteins is found inside every cell in the body, where these proteins do nothing but wait. Then, when a virus bursts in, it seeds a crystal and proteins instantly clump around it, forming a scaffold for enzymes known as caspases to activate and immediately initiate cell death. (Caspases must bind to kill the cell; it is their proximity to each other that activates them.) The type of cell death caused by this mechanism is called pyroptosis and, unlike apoptosis (programmed cell death), it triggers inflammation.

“What we found, in essence, is that the Cells are literally waiting to die all the time.,” says Randal Halfmanassociate researcher at the Stowers Institute for Medical Research. Halfmann supervised the work, which was published in eLife in September.

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Historically, scientists have studied the folded structures of proteins to understand their function individually. But “we’re in this explosion of discovery, realizing that these individual molecules that we’ve studied so well are coming together to form larger structures that aren’t bound by membranes,” he says. Mr. Allan Drummondmolecular biologist at the University of Chicago, who was not involved in the study. This new understanding has driven “new kinds of ways of thinking about cellular function and decision-making by cells, new ways of storing energy, etc.”

The study, which was performed in living yeast cells and human cell lines, illustrates how the proteins act collectively forming a crystal that brings together caspases to activate the cell death program and allow the cell to make a rapid life or death decision. It also provides an example of how solid protein clumps, which are generally considered pathological (as in Alzheimer’s disease), can be essential to function: “To be useful, their whole job is to be an irreversible, downhill, spontaneous reaction that allows the cell to make decisions that include killing it,” Drummond says. The speed of the decision is key: If the cell relies on more traditional signaling pathways that activate genes in response to an infection, an agile virus could take control of the cell’s protein-making machinery before the cell has a chance to respond.

Although structural biologists had studied this type of protein behavior in test tubes, “what was really missing was: ‘Does this really happen in the cell?'” he says. Bostjan Kobeprotein structural biologist at the University of Queensland in Australia. “That’s why [Halfmann’s] “The work was really interesting because it approached the problem from a completely different angle.”

Halfmann’s team observed that these immune proteins normally remain soluble but, if given enough time (over the course of life), they will crystallize spontaneously, failing in a way that leads to cell death and inflammation. “What this means is that if you wait long enough, every cell will die through this mechanism because even if a virus doesn’t enter the cell, it will happen with some frequency spontaneously,” says Halfmann. (Of course, cells can die by other mechanisms, such as apoptosis, in the first place.)

Halfmann’s team quantified the driving force for these proteins to crystallize in different types of human cells and found that their concentration correlates with the rate of cell renewal in our body. For example, some blood cells are replaced every few days, while neurons typically last a lifetime. The faster cells normally regenerate, the more immune proteins they tend to have, suggesting that this spontaneous activation process could be responsible for killing them.

These results suggest that these immune proteins could be contributing to the low-grade inflammation that accompanies aging. Finding ways to prevent proteins from crystallizing could potentially extend the lifespan of cells and reduce aging-related inflammation, but the trade-off would be a weaker immune system, Halfmann says.

This characteristic of the immune system is very old. It is found in early animals, such as sponges, and even exists in bacteria, from which we probably inherited it. It is found specifically in some bacteria that live in close-knit communities. “If you are a single-celled organism, there is no impulse to commit suicide,” says Halfmann. “But when you’re part of a community and you’re compromised by a phage [a virus that kills bacteria]”so it absolutely makes sense to kill yourself because you’re related to everyone around you, and that’s where these proteins seem to have evolved.”

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