Researchers Show Important Protein in Innate Immune System Has Six Different Forms, Possibly Many Different Roles in the Body – ScienceDaily

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Shigella The bacteria can infect humans, but not mice. in the March 29 issue nature, a team from UConn Health explains why. Their findings may explain the diversity of a major weapon of our immune system.

Shigella infection causes fever, stomach pain, and sometimes prolonged bloody diarrhea for up to a week. The bacteria infects 450,000 people each year in the United States alone. Although most people recover on their own, children and those with weakened immune systems are at risk of spreading shigella infection to the bloodstream and causing kidney damage. Shigella infection is an important cause of disease and disability, but the bacterium is difficult to study because it only infects primates like humans and monkeys — not animals that are easier to study in the laboratory. The bacteria cannot infect typical laboratory animals such as mice.

Previous research has looked at how shigella interacts with gazdermin-B, an important part of our immune system that helps protect us from infection. Gasdermin-B is a member of the proteome family called gasdermin, which includes gasdermin-A, -B, -C, -D, -E and -F. It used to be thought that when gazdermin-B detects an invader, such as a bacteria, it begins to poke holes in the cell wall, causing them to burst and release chemicals that stimulate inflammation and call for boosts from the immune system. But previous research studies on Gasdermin-B have been contradictory. Some have confirmed its role in cell death during infection, but others have disputed the idea.

Jianbin Ruan, an immunologist at UConn University School of Medicine, and a team of colleagues from UConn Health wanted to clarify whether gasdermin-B actually causes cell death in the event of microbial invasion. They also wanted to know why she wouldn’t do it when Shigella is the invader.

The team needed to take a closer look at Gasdermin-B. They took out the protein, purified it, and then cooled it to temperatures so low that it would remain stable while electron microscopy images of it.

said Chengliang Wang, a research fellow in Ruan’s lab and first author of the study.

Their research confirms previous research and provides evidence that Shigella bacteria hold onto a specific part of Gazdermin-B in humans. However, the murine version of the protein has a different shape that prevents shigella from attaching to it, resulting in rapid shedding of the bacteria and preventing infection. This finding helps explain why Shigella was unable to infect mice.

Because human gasdermin-B can be made into six slightly different proteins, or isoforms, the team expressed all six, then looked at how these isoforms behaved inside cells, and found something surprising: Some gasdermin-B isoforms actually punched holes. . to cause cell death – but the other isoforms did not.

“Before, people didn’t understand why the studies were contradictory to each other. We showed that only two gazdermin-B isoforms cause pyroptosis, or cell death,” says Ruan. These two isoforms contain a specific protein fragment that is absent in the other gazdermin-b isoforms, as revealed by the cryo-electron microscopy structure.

This discovery may explain many mysteries of cell death and life. Cancer cells, for example, are known for their longevity and are less likely to die of laryngitis. It may be that these cancer cells express only gasdermin-B isoforms that do not make holes in their cell walls.

However, we do not yet know what these other isoforms do. It may be that different isoforms of gasdermin-B play important and distinct roles depending on where they are located in the body, and different cell types preferentially express different isoforms.

“The protein structures discovered by our team have major implications for drug development. Specifically, they could help design small-molecule drugs that modulate the activity of gazdermin-B,” explains Ruan. “These drugs can be used to treat a range of conditions, including cancer, inflammatory and autoimmune diseases, and infectious diseases by either suppressing or enhancing the immune response. Thus, our findings herald the development of new therapies to address these pressing medical ailments.” Need. “

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