Fig. 1. Non-canonical inflammasomes and non-canonical inflammasome-activated inflammatory signaling pathways.
(A) Domain structure of mouse caspase-11 and human caspase-4 and caspase-5. Caspase-11, caspase-4, and caspase-5 have same domain structure composed of amino-terminal CARDs, followed by large (p20) and small (p10) catalytic domains, but different amino acid lengths; 373, 377, and 434 amino acids, respectively. (B) Sensing of LPS by caspase-4/5/11. Caspase-4/5/11 senses cytosolic LPS by direct interaction between CARDs of caspase-4/5/11 and lipid A of LPS, which leads to the formation of LPS-caspase-4/5/11 complexes. (C) Non-canonical inflammasome-activated inflammatory signaling pathways. LPS derived from gram-negative bacteria is internalized into the host cells, and caspase-4/5/11 directly senses the cytosolic LPS, leading to the formation of LPS-caspase-4/5/11 complexes and caspase-4/5/11 non-canonical inflammasomes by oligomerization through CARD-CARD interaction. Caspase-4/5/11 non-canonical inflammasomes activated by autoproteolytic cleavage induce the proteolytic cleavage of GSDMD and the generation of GSDMD pores, resulting in pyroptosis of the cells. Caspase-4/5/11 non-canonical inflammasome activation induces NLRP3 inflammasome-mediated proteolytic activation of caspase-1, leading to the proteolytic maturation and secretion of IL-1β and IL-18 through GSDMD pores. CARD, caspase recruitment domain; LPS, lipopolysaccharide; GSDMD, gasdermin D; IL, interleukin.
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