Title: Innate immunity to cytosolic bacteria: pyroptosis and beyond
Speaker: Shao Feng, National Institute of Biological Sciences, Beijing
Venue: Room 335, Building B2, University Town Campus
Time: March 14, Thursday, 15:00
Lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria, is long known to be sensed by the plasma membrane-bound TLR4 receptor. Ligation of TLR4 by the lipid A of LPS stimulates NF-κB and IRF-mediated inflammatory cytokine production. Recently, we showed that caspase-11, 4 and 5 are cytosolic immune receptors for LPS and activated by direct binding to its lipid A part. Like caspase-1 activation by the canonical inflammasome, caspase-11/4/5 activation induces pyroptosis, both of which are critical for antibacterial defense and development of immunological diseases. Caspase-11/4/5 and caspase-1 cleave Gasdermin D (GSDMD) to release the autoinhibition of its N-terminal domain that bears an intrinsic pore-forming activity for executing pyroptotic cell death. Gsdmd-/- mice are susceptible to various bacterial infections and also resist LPS-induced septic shock. GSDMD belongs to a large Gasdermin family sharing the pore-forming domain. Another family member GSDME whose expression is silenced in most cancer cells, is activated by caspase-3 cleavage; inflammatory damages caused by GSDME-mediated pyroptosis is the major determinant for the toxicity of those DNA-damaging chemotherapy drugs. Lastly, we discover that ADP-heptose, the precursor for LPS inner core oligosaccharide, is recognized in host cytosol by a novel kinase receptor ALPK1. Like lipid A-activated TLR4, ADP-heptose-activated ALPK1 potently stimulates NF-κB-dependent inflammatory responses both in cells and mice. These findings shift the paradigm of immune sensing of LPS and antibacterial defense, and open several new areas of research on innate immunity and pyroptosis-mediated inflammation. The cell-entry property of ADP-heptose also suggests a new way of modulating immune responses in mammals.
Announced by the School of Medicine