UT Southwestern biochemist and Breakthrough Award Dr. Zhijian “New James Study” Chen explains a long-standing question in the field of innate immunity.
Scientists have long wondered how a single protein, NLRP3, may contribute to inflammation in response to a wide range of seemingly unrelated stimuli.
Dr. Chen, a professor of molecular biology and director of the UT Southwestern Center for Research on Inflammation, received the 2019 Life Sciences Prize for identifying the cGAS DNA-sensitive enzyme (cyclic GMP-AMP synthase), which is the innate immune response within cells. .
In the current study, published today in NatureDr. Chen explored another pathway of the immune system, which includes the NLRP3 protein, which plays an important role in assembling a cell of a multi-protein complex called inflammation. In response to a host of harmful agents that range from toxins to cholesterol crystals, inflammation causes a path to inflammatory cell death or pyroptosis from the Greek word pyro, which means fire. Inflammation also increases the body's production of immune systems, such as interleukins, which help in the body's immune response.
In addition, the NLRP3 protein underlies inflammation in a group of auto-inflammatory diseases, called cryopirin-associated recurrent syndromes (CAPS), which includes familial cold auto-inflammatory syndrome (FCAS), gout, and a form of inflammation of brain cells associated with Alzheimer's disease.
“A multi-year issue in this area is how NLRP3 can be activated by many different agents, who apparently don’t have any chemical or structural similarities,” said Dr. Chan, an investigator at the Howard Hughes Medical Institute, who holds George L. McGregor — the distinguished chairman in the field of biomedical science, as well as a professor at the Center for Genetic Defense of the Enemy in Southwest Utah. "These results provide a new pathway for the development of therapeutic drugs that target the NLRP3 pathway for the treatment of inflammatory diseases."
Through a combination of biochemical, imaging and genetic approaches, Dr. Chen and a doctoral researcher Dr. Jueqi Chen, lead author and unrelated to the study, have discovered previously unknown structural changes in cells.
They found that various stimuli cause cellular organelles, called the trans-Golgi network (TGN), to divide into giant vesicles or fluid-filled sacs. These vesicles contain a special lipid component (PI4P) that binds to a specific region of NLRP3. This binding causes a series of events leading to the activation of inflammation.
“The susceptibility of NLRP3 is unique in that it can be triggered by a large number of stimuli,” said Dr. Chen. “This study finds that instead of directly recognizing harmful agents, the malignant tumor NLRP3 detects structural changes caused by a number of different agents that cause cell damage. In fact, NLRP3 activation is reminiscent of a “watchdog model” that plants use to combat a variety of threats by monitoring modified host targets, the so-called approach caused by a pathogenic change.
“By associating with trans-Golgi disassembled vesicles as a“ modified me, ”NLRP3 indirectly perceives a large number of molecules associated with pathogens and hazards,” he added.
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Jueqi Chen et al. PtdIns4P on the trans-Golgi disperse network mediates the activation of the inflammatory process NLRP3, Nature (2018). DOI: 10.1038 / s41586-018-0761-3