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Molecular alarm system ensures body’s first response to an attack will be a healthy one

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Posted March 8, 2017

For bacteria and other would-be microscopic invaders, your body is like a tightly guarded fortress.

Each of your 37 trillion cells is equipped with proteins that are primed to detect unfamiliar molecules. When triggered, they set off a cascade of reactions that tell your body to mount an immediate response.

Daniel Capelluto works on an experiment with Wen Xiong (far right), and Tuo-Xian Tang (center), who are visiting Ph.D. students. The students are collaborating with Capelluto on the research.

This molecular alarm system is a feature of what biologists call “innate immunity,” your body’s first line of defense against external threats.

However, this system’s sensitivity can be a double-edged sword. The longer a cell sets off its alarm signal, the more severe the body’s immune response will be.

If the alarm’s not shut off at the appropriate time, a healthy reaction like inflammation will start to spike at dangerous levels — a condition that’s been closely linked to heart disease, allergies, obesity, degenerative brain diseases, and cancer.

Until recently, scientists were stumped as to what could be going on inside our cells to keep this alarm system in check. But a research team based at Virginia Tech may have just uncovered a key piece of the molecular puzzle: a helper protein called TIRAP that cells can render inactive when the defensive response becomes harmful to the body.

Their landmark findings, which have implications for autoimmune diseases, such as rheumatoid arthritis and psoriasis, were recently published in Scientific Reports.

“Chronic inflammation conditions are caused by overreactions in our immune response,” said Daniel Capelluto, an associate professor of biological sciences in the College of Science, a Fralin Life Science Institute and Center for Soft Matter and Biological Physics affiliate, and fellow in the Biocomplexity Institute of Virginia Tech. “Knowing exactly how this signal is switched on and off inside our cells gives us a much more reliable means of controlling it.”

Normally, the surface membranes of our innate immune cells are enriched with TIRAP proteins, poised to receive and transmit emergency signals from the outside.

Unfortunately, TIRAP isn’t equipped with an off switch. It will continue to sound the alarm beyond the bounds of a healthy immune response unless it is forcibly removed from our cell membranes.

Using high-resolution imaging techniques and some carefully selected cellular mutations, Capelluto’s team was able to demonstrate that cells employ a protein modification process to keep TIRAP under control.

Their observations show that this protein modification causes TIRAP to undergo a structural rearrangement, removing its capacity to associate with our cell membranes. With their “landing gear” disabled, the now-inert TIRAP molecules drift into the cell’s interior to be broken down.

“This discovery could give drug developers a new way to keep an overreacting immune system in check,” said Carla Finkielstein, Capelluto’s long-time collaborator, an associate professor of biological sciences in the College of Science, a Fralin Life Science Institute affiliate, and fellow in the Biocomplexity Institute of Virginia Tech. “Blocking or enhancing TIRAP’s ability to bond inside our cells will allow us to reconfigure the base level of our innate immune reaction, ensuring that our body’s first response to an attack will be a healthy one.”

This project was developed in collaboration with Virginia Tech graduate students Xiaolin Zhao, Wen Xiong, and Tuo-Xian Tang; former postdoctoral associate Shuyan Xiao; Jeffrey Ellena, a senior scientist at the University of Virginia; and Geoffrey Armstrong, a research associate at the University of Colorado-Boulder, were also on the research team.

Source: VirginiaTech

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