Discovery of the cytosolic immune receptor for bacterial LPS and its downstream pyroptosis execution protein GSDMD

Abstract：These studies for the first time identify and characterize three cytosolic innate immune receptors or sensors for major bacterial molecular pattern molecules, as well as their downstream pyroptosis-execution protein GSDMD. The three immune receptors (NAIPs, Pyrin and caspase-11/4/5) activate a form of programmed cell death called pyroptosis, but the underlying mechanism was unknown for more than 20 years. Indeed, the nature of pyroptotic cell death was not clear and it was long regarded as a special form of apoptosis. The work has now solved the mystery by identifying the novel gasdermin-D (GSDMD) protein with a novel membrane-disrupting pore-forming activity. With the identification of GSDMD, the nature of pyroptosis is now well established and agreed as an immunogenic necrotic cell death. Formation of the GSDMD membrane pores is also required for extracellular secretion of caspase-1-processed IL-1, solving a longstanding mystery about noncanonical secretion of inflammatory cytokines in immunology research. As the intracellular LPS-sensing pathway is required for septic shock, identification of GSDMD brings a novel concept that excessive and systemic pyroptosis is the determinant for sepsis, providing a novel route for drug development. Moreover, the gasdermin family of protein is not only the core execution protein and molecular marker for pyroptotic cell death, but also represents the first type of pore-forming protein present in the cytosol of mammalian cells.