清华大学生物论坛“云上学术”系列讲座之第1期预告
时间：2020-05-12 10:00-11:00
主讲人：Zhigao Wang,PhD（University of Texas Southwestern Medical Center）
主题：Paving the necroptosis pathway with chemical compounds and genetic screens
直播地址：Zoom (ID:5305315446)
Biography:
Dr. Wang received his B.S. degree from the Department of Biochemistry from Wuhan University in 1994. He did his PhD training in the lab of Dr. Eric Olson at the University of Texas Southwestern Medical Center, where he characterized the function of myocardin as a master regulator in smooth muscle gene expression and phenotypic modulation. In 2004, he joined the lab of Dr. Xiaodong Wang for his postdoctoral training at the same institute, where he assisted the identification and characterization of a necroptosis blocking compound named necrosulfonamide (NSA). Using NSA as a tool, he revealed an important role of a mitochondria phosphatase PGAM5 in necroptosis and oxidative cell death. In 2012, he became an assistant professor in the Department of Molecular Biology at UT Southwestern Medical Center, and was named the Virginia Murchison Linthicum Scholar in Medical Research and the Cancer Prevention & Research Institute of Texas Scholar. As an independent investigator, his lab continues to dissect the molecular mechanisms of necroptosis using chemical and genetic tools, aiming to develop chemical compounds that potentially will help treat necroptosis-associated diseases.
Abstract:
Necroptosis is a regulated necrotic cell death pathway involved in many human pathologic conditions, including infection, tissue injury and cancer. Tumor necrosis factor (TNF)-induced necroptosis requires receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3), and a pseudokinase mixed lineage kinase domain-like protein (MLKL). Our work demonstrate that MLKL forms disulfide bond-dependent amyloid-like fibers to promote necroptosis. Importantly, MLKL disulfide bond formation is tightly controlled by the cellular antioxidant enzyme thioredoxin 1. Knockdown or chemical inhibition of thioredoxin 1 leads to spontaneous necroptosis in cancer cells expressing high levels of MLKL. Furthermore, we discovered a novel necroptosis-blocking compound NBC1 from a compound library screen, and identified its target as the molecular chaperone Hsp70. Mechanistically, Hsp70 uses two cysteines in its substrate-binding domain to facilitate MLKL tetramers polymerize into amyloid-like fibers to activate necroptosis. These results generate significant insights into the molecular mechanisms of necroptosis and provide new therapeutic strategies against necroptosis-associated diseases.
