Characterization and Identification of the Protease Responsible for GSDMB Cleavage
Annabelle Malinowski, Justin Hansen, Maarten de Jong, and Neal Alto
UT Southwestern Medical Center, Department of Microbiology, Dallas TX 75235
The mammalian immune system contains a diverse arsenal of defense mechanisms against pathogens. Pyroptosis, programmed inflammatory cell death, is a cellular response to inflammasome activation by various pathogens and danger associated molecular patterns (DAMPs). Cytosolic contents and inflammatory cytokines are released, activating neighboring immune cells. The Gasdermin (GSDM) family of proteins are the executioners of pyroptosis. GSDM proteins are composed of two domains: an N-terminal (NT) domain that can oligomerize and form pores in membranes and a C-terminal (CT) domain that is responsible for autoinhibition of the NT-domain. Cleavage of GSDMD, by inflammatory caspases 1 and 4/5, is necessary for cytokine release and cell death. While the GSDMD mediated cell death mechanism has been studied extensively, this work studies the function of a less characterized protein, GSDMB. Among all human caspases, GSDMB is cleaved by caspases 3, 6, and 7 after 88DVND91 within the –NT domain, which does not correspond to the predicted interdomain linker. Caspase 3/6/7 cleavage yields a truncated GSDMB-NT domain that most likely cannot oligomerize and form pores. Thus the protease(s) responsible for cleavage of GSDMB at its interdomain linker remain unknown. This presentation will focus on the efforts to identify this protease and its functional consequences in cell death during pathogen infection.
