| text | Caspase-5 (CASP5), along with caspase-4 (CASP4), is activated in response to cytosolic bacterial lipopolysaccharide (LPS) (Shi J et al. 2014, 2015; Vigano E et al. 2015; Lagrange B et al. 2018). Once activated, CASP5 cleaves gasdermin D (GSDMD) at aspartic acid 275 (D275) within the central linker region, generating a 31-kDa N-terminal fragment (GSDMD(1–275)) and a 22-kDa C-terminal fragment (GSDMD(276–484)) (Shi J et al. 2015; Ding J et al. 2016; Liu Z et al. 2019; Yang J et al. 2018; Kuang S et al. 2017; Zhao Y et al., 2018; Wang K et al., 2020). The N-terminal fragment has pore-forming activity and inserts into lipid membranes to form 10–16 nm pores, leading to pyroptotic cell death (Liu X et al., 2016; Ding J et al., 2016; Sborgi L et al., 2016; Aglietti RA et al., 2016; Feng S et al. 2018). The C-terminal fragment maintains an autoinhibitory interaction with the N-terminal domain in full-length GSDMD, and its cleavage by inflammatory caspases, CASP4 or CASP5, releases this inhibition, enabling pyroptosis (Shi J et al. 2015; Ding J et al. 2016; Liu Z et al. 2019; Yang J et al. 2018; Kuang S et al. 2017; Wang K et al., 2020). Further, GSDMD binding can enhance the catalytic activity of CASP4 by stabilizing its active dimer, suggesting a similar mechanism may apply to CASP5 (Wang K et al. 2020). The expression of GSDMD (1-275), but not the C-terminal fragment of GSDMD (276-484), induced pyroptosis in human embryonic kidney 293 (HEK293) cells (Shi J et al. 2015). In addition to causing membrane rupture, GSDMD pores allow for the secretion of proinflammatory cytokines IL-1β and IL-18, amplifying the immune response in mammals (Shi J et al. 2015; Kayagaki N et al., 2015; Ding J et al. 2016; Evavold CL et al. 2018; reviewed by Broz P et al., 2020; Liu X et al., 2021). Caspase-11, the murine ortholog of human CASP4 and CASP5, similarly cleaves Gsdmd, triggering pyroptosis in mice indicating a conserved mechanism of GSDMD-mediated cell death across species (Shi J et al. 2015; Kayagaki N et al. 2015).
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