Caspase-4 (CASP4) is activated by autoproteolysis upon direc...

created [InstanceEdit:9948158] Shamovsky, Veronica, 2025-05-16
dbId 9948147
displayName Caspase-4 (CASP4) is activated by autoproteolysis upon direc...
literatureReference
modified [InstanceEdit:9963576] Shamovsky, Veronica, 2025-08-14
schemaClass Summation
text Caspase-4 (CASP4) is activated by autoproteolysis upon direct sensing of intracellular bacterial lipopolysaccharide (LPS) (Shi J et al. 2014, 2015; Kajiwara Y et al. 2014; Casson CN et al. 2015; Vigano E et al. 2015; Lagrange B et al. 2018; Wang K et al. 2020). Once activated, CASP4 cleaves gasdermin D (GSDMD), which is also a substrate of CASP1, CASP5, and Casp11, a murine homolog of human CASP4/CASP5 (Shi J et al., 2015; Kayagaki N et al., 2015; Zhao Y et al., 2018; Wang K et al., 2020). This cleavage releases a cytotoxic N-terminal fragment (GSDMD(1?275)) that oligomerizes to form pores in lipid membranes, and a C-terminal fragment (GSDMD(276?484)) that normally inhibits the pore-forming activity through inhibitory binding to the N-terminus (Shi J et al., 2015; Kayagaki N 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). The N-terminal fragment forms membrane pores of 10-20 ?nm, triggering pyroptotic cell death and facilitating the release of IL-1? and IL-18 in mammalian cells (Liu X et al., 2016; Ding J et al. 2016; Sborgi L et al. 2016; Aglietti RA et al., 2016; Evavold CL et al. 2018; Downs KP et al. 2020; Xia S et al., 2021; Dai Z et al., 2023). Expression of GSDMD(1?275) alone is sufficient to induce pyroptosis, while the C-terminal fragment blocks this process (Shi J et al. 2015). Further, GSDMD binding to CASP4 enhances CASP4 catalytic activity by stabilizing the dimeric active form (Wang K et al. 2020).
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