Gasdermin D pore structure reveals preferential release of mature interleukin-1

Shiyu Xia, Zhibin Zhang, Venkat Giri Magupalli, Juan Lorenzo Pablo, Ying Dong, Setu M. Vora, Longfei Wang, Tian-Min Fu, Matthew P. Jacobson, Anna Greka, Judy Lieberman, Jianbin Ruan () and Hao Wu ()
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Shiyu Xia: Boston Children’s Hospital
Zhibin Zhang: Boston Children’s Hospital
Venkat Giri Magupalli: Boston Children’s Hospital
Juan Lorenzo Pablo: Brigham and Women’s Hospital
Ying Dong: Boston Children’s Hospital
Setu M. Vora: Boston Children’s Hospital
Longfei Wang: Boston Children’s Hospital
Tian-Min Fu: Boston Children’s Hospital
Matthew P. Jacobson: University of California San Francisco
Anna Greka: Brigham and Women’s Hospital
Judy Lieberman: Boston Children’s Hospital
Jianbin Ruan: Boston Children’s Hospital
Hao Wu: Boston Children’s Hospital

Nature, 2021, vol. 593, issue 7860, 607-611

Abstract: Abstract 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-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis1–9. 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-110. 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-1β and IL-18 over that of their precursors. Consistent with these findings, living—but not pyroptotic—macrophages preferentially release mature IL-1β 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.

Date: 2021
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DOI: 10.1038/s41586-021-03478-3

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