| First Author | Wang K | Year | 2020 |
| Journal | Cell | Volume | 180 |
| Issue | 5 | Pages | 941-955.e20 |
| PubMed ID | 32109412 | Mgi Jnum | J:296118 |
| Mgi Id | MGI:6467703 | Doi | 10.1016/j.cell.2020.02.002 |
| Citation | Wang K, et al. (2020) Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell 180(5):941-955.e20 |
| abstractText | The pyroptosis execution protein GSDMD is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain from GSDMD-C-terminal domain. How the caspases recognize GSDMD and its connection with caspase activation are unknown. Here, we show site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-form autoprocessed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a beta sheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the beta sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode. Our study reveals an unprecedented substrate-targeting mechanism for caspases. The hydrophobic interface suggests an additional space for developing inhibitors specific for pyroptotic caspases. |
