| First Author | Devant P | Year | 2021 |
| Journal | Sci Immunol | Volume | 6 |
| Issue | 62 | PubMed ID | 34734155 |
| Mgi Jnum | J:341007 | Mgi Id | MGI:7486393 |
| Doi | 10.1126/sciimmunol.abh3567 | Citation | Devant P, et al. (2021) Evolution-inspired redesign of the LPS receptor caspase-4 into an interleukin-1beta converting enzyme. Sci Immunol 6(62):eabh3567 |
| abstractText | 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. Herein, we test this hypothesis by studying caspases that regulate inflammasome-dependent inflammation. Several caspases differ in their ability to recognize bacterial LPS and cleave interleukin-1beta (IL-1beta). No caspase is known to contain both activities, yet distinct caspases with complementary activities bookend an LPS-induced pathway to IL-1beta cleavage. Using caspase-1/4 hybrid proteins present in canines as a guide, we identified molecular determinants of IL-1beta cleavage specificity within 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-1beta cleavage and release, independent of inflammasomes. We identified caspase-4 homologues in multiple carnivorans which 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. |
