Zhirong Zhang

Title : Distinct changes in endosomal composition promote NLRP3 inflammasome activation

Abstract:

Inflammasome complexes are pivotal in the innate immune response to pathogens and other danger signals. The NLRP3 inflammasome is activated in response to a broad variety of cellular stressors, including COVID-19 infection. Most of the stimuli act in a potassium efflux-dependent manner but a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill-defined. Here we show that NLRP3 activators disrupt endosome-TGN retrograde transport (ETRT) and lead to localization of NLRP3 to endosomal vesicles. Genetic and pharmacologic perturbation of ETRT leads to accumulation of phosphoinositol-4-phosphate (PI4P) in endosomes to which NLRP3 is recruited. Disruption of ETRT potentiates NLRP3 inflammasome activation in murine and human macrophages in vitro. Mice with defects in ETRT in the myeloid compartment are more susceptible to LPS-induced sepsis showing enhanced mortality and IL-1β serum levels as compared to control animals. Our study thus uncovers that changes in endocytic trafficking mediate NLRP3-dependent inflammatory responses. 

Biography:

Dr. Zhirong Zhang is a senior scientist at the Institute of Genetics and Molecular and Cellular Biology (IGBMC), Strasbourg, France. He obtained his PhD degree under the mentorship of Prof. Jiahuai HAN, who pioneers the MAPK signaling and programmed cell death pathway, at Xiamen University in Xiamen, China. After PhD, he joined the laboratory of Romeo RICCI at IGBMC for post-doctoral training. His current research interest focuses on the understanding of molecular mechanism underlying the activation NLRP3 inflammasome in vitro and in vivo, which has been widely implicated in many human inflammatory diseases, including infectious diseases (COVID-19 infection).