Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 62, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abh3567
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Funding
- NIH [AI133524, AI093589, AI116550, P30DK34854]
- Burroughs Wellcome Fund
- Boehringer Ingelheim Fonds
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Innate immune signaling pathways involve multiple proteins that promote inflammation, with the complexity being a prerequisite for pathway design. Through studying caspases that regulate inflammation, it was found that different caspases can complement each other, condensing a multistep pathway into a single protein.
Innate immune signaling pathways comprise multiple proteins that promote inflammation. This multistep means of information transfer suggests that complexity is a prerequisite for pathway design. Here, we test this hypothesis by studying caspases that regulate inflammasome-dependent inflammation. Several caspases differ in their ability to recognize bacterial lipopolysaccharide (LPS) and cleave interleukin-1 beta (IL-1 beta). No caspase is known to contain both activities, yet distinct caspases with complementary activities bookend an LPS-induced pathway to IL-1 beta cleavage. Using caspase-1/4 hybrid proteins present in canines as a guide, we identified molecular determinants of IL-1 beta cleavage specificity within human and murine caspase-1. This knowledge enabled the redesign of human caspase-4 to operate as a one-protein signaling pathway, which intrinsically links LPS detection to IL-1 beta cleavage and release, independent of inflammasomes. We identified caspase-4 homologs in multiple carnivorans that display the activities of redesigned human caspase-4. These findings illustrate natural signaling pathway diversity and highlight how multistep innate immune pathways can be condensed into a single protein.
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