| Caspase‑4 is a human inflammatory caspase of the caspase‑1/4/5/11 family that functions as a thiol protease with stringent Asp‑P1 specificity and serves as a core effector of the non‑canonical inflammasome, directly linking cytosolic lipopolysaccharide (LPS) recognition to gasdermin D–dependent pyroptosis and downstream cytokine release. The zymogen contains an N‑terminal caspase recruitment domain (CARD) for oligomerization and LPS binding, followed by a conserved protease region that is split into large p20 and small p10 subunits upon activation; dimerization and auto‑processing at defined Asp residues in the interdomain linker generate p32/p9 and p34/p9 species that are catalytically competent and together constitute the active enzyme forms responsible for gasdermin D cleavage and, under specific conditions, IL‑1β maturation. In the non‑canonical inflammasome, caspase‑4 is activated by direct binding of the lipid A moiety of cytosolic LPS to its CARD without an upstream pattern-recognition sensor, resulting in caspase‑4 oligomerization, auto‑processing and selective recognition of the C‑terminal domain of gasdermin D through a hydrophobic exosite interface that lies outside the classical tetrapeptide substrate groove; this interaction allows precise cleavage of gasdermin D, liberates the N‑terminal pore-forming fragment and triggers membrane permeabilization and pyroptotic cell death. Structural analyses of caspase‑4–gasdermin D complexes show that autoprocessed p20/p10 heterodimers further dimerize into heterotetramers and that exosite-mediated docking of gasdermin D‑C is required for cleavage, explaining the narrow substrate spectrum of caspases in innate immunity and identifying a non‑catalytic pocket that can be exploited for drug development to control pyroptosis in inflammatory disease. Caspase‑4 not only drives pyroptosis but also processes IL‑18 via a similar exosite-dependent mechanism, enabling IL‑18 release through gasdermin pores and supporting mucosal barrier defense, and in human monocytes caspase‑4 and caspase‑5 mediate a one‑step non‑canonical inflammasome activation pathway in response to LPS that couples pyroptosis with rapid IL‑1 family cytokine secretion. Caspase‑4 activity also influences canonical inflammasomes: gasdermin D–mediated pore formation and ionic flux downstream of caspase‑4 can indirectly activate NLRP3 and NLRP6 complexes, leading to caspase‑1 activation and maturation of IL‑1β and additional IL‑18, integrating non‑canonical sensing of cytosolic bacterial products with broader inflammasome network responses. In barrier tissues, caspase‑4 plays specialized roles; in human gingival fibroblasts exposed to Td92, a surface protein of Treponema denticola, cathepsin G binds and activates caspase‑4, leading to gasdermin D–dependent pyroptosis and robust IL‑1α production and secretion, which contribute to periodontal inflammation and host defense against this pathogen. In colonic epithelium, caspase‑4 activity restricts intracellular replication of enteric bacteria such as Salmonella by inducing pyroptosis and extrusion of infected cells into the gut lumen, while IL‑18 processing promotes recruitment and activation of immune cells and mucosal inflammation, underscoring its dual function in pathogen clearance and inflammatory tissue damage. Caspase‑4 is also implicated in sterile inflammatory and neurodegenerative contexts, including ER stress–induced death and cytotoxic amyloid precursor protein peptide–induced death, and an Apaf‑1/caspase‑4 pyroptosome has been described as a mediator of mitochondrial permeability transition–triggered pyroptosis, linking caspase‑4 to mitochondrial stress responses. |
