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A new study addresses the long-standing secrets of inborn immunity

UT Southwest biochemist and winner of Dr. Zhijian "James" Chen's most recent study responds to a long-standing question in the area of ​​congenital immunity.

Scientists have long known how one protein, NLRP3, can promote inflammation in response to a wide range of seemingly unrelated stimuli.

Dr. Chen, Professor of Molecular Biology and Director of the UT Southwestern Fire Rescue Research Center, received this year's breakthrough 2019 Life Sciences award for identifying the enzyme cGAS (cyclic GMP-AMP synthase) that radiates the alarm to the innate immune response inside the cells.

The current study, which was released today in 2006 Nature, Dr. Chen examined another pathway of the immune system that includes the NLRP3 protein, which is an important tool in assembling a cell complex of multiprotein called inflammation. In response to a number of harmful substances ranging from toxins to cholesterol crystals, ignition causes a pathway of inflammatory cell death or pyroptosis from the Greek word pyro, which means fire. Inflammmasm also increases the production of organs of the immune system, such as interleukins, which help immune responses to the body.

In addition, the NLRP3 protein is associated with inflammation in a group of autoimmune diseases, called periodic cryptothyrine-associated syndromes (CAPS), which include familial cold syndrome syndrome (FCAS), dysentery and inflammation of brain cells associated with Alzheimer's disease.

"The long-standing question in this area is how NLRP3 can be activated by many different actors who did not seem to have any chemical or structural similarity," Dr. Chen, the Howard Hughes Medical Institute, which holds the George L. MacGregor Distinguished Department of Biomedical Science, as well as a professor at the Center for Host Defense Genetics at UT Southwestern. "These findings provide a new pathway for the development of therapeutics that focus on the pathway of NLRP3 for the treatment of inflammatory diseases."

Through a combination of biochemical, imaging and genetic approaches, Dr. Chen and the postdoctoral researcher Dr. Jueqi Chen, lead author of the study and no relationship, discovered previously unknown structural changes within the cells.

They have found that diverse stimuli cause cellular organelles called the trans-Golgi network (TGN) to disintegrate into giant vesicles or fluid-filled bags. These vesicles contain a special lipid component (PI4P) that binds to a specific NLRP3 region. This binding triggers a series of events leading to inflammation activation.

"Inflammation of the NLRP3 is unique because it can be triggered by a lot of stimuli," Dr. Chen. "This study found that, rather than detecting harmful substances directly, the inflammation of the NLRP3 detects a structural change caused by a number of different agents that cause cell damage. In fact, activation of the NLRP3 recalls the" protective model "used by plants to combat various threats by monitoring the changed host targets, pathogen-induced altered self-access.

"Linking to the dismantled trans-Golgi network vesicles as a" modified I ", NLRP3 indirectly feels a large number of pathogenic and dangerous molecules," he added.


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