Other
13 Authors
- Vora SM,
- Fu TM,
- Wu H,
- Xia S,
- Pablo JL,
- Wang L,
- Greka A,
- Jacobson MP,
- Magupalli VG,
- Zhang Z,
- Lieberman J,
- Ruan J,
- Dong Y
| First Author | Xia S | Year | 2021 |
| Journal | Nature | Volume | 593 |
| Issue | 7860 | Pages | 607-611 |
| PubMed ID | 33883744 | Mgi Jnum | J:319941 |
| Mgi Id | MGI:6867106 | Doi | 10.1038/s41586-021-03478-3 |
| Citation | Xia S, et al. (2021) Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 593(7860):607-611 |
| abstractText | As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1beta and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis(1-9). Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1(10). When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1beta and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1beta upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel. |
