Journal Article

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

Vora, Setu M., Wu, Hao, Wang, Longfei, Fu, Tian-Min, Dong, Ying, Greka, Anna, Zhang, Zhibin, Jacobson, Matthew P., Ruan, Jianbin, Magupalli, Venkat Giri, Lieberman, Judy, Xia, Shiyu, Pablo, Juan Lorenzo

2021

Overview

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 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-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. A cryo-electron microscopy study of the gasdermin D pore reveals a model of pore assembly and a charge-based mechanism for the preferential release of mature cytokines.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/250/262 / 631/535/1258/1259 / Animals / Caspase 1 - metabolism / Caspase-1 / Cell organelles / Channel pores / Cryoelectron Microscopy / Cytokines / Electron microscopy / Humanities and Social Sciences / Humans / Hydrophobicity / Immune system / Inflammasomes / Inflammasomes - chemistry / Inflammation / Innate immunity / Interleukin 1 / Interleukin-1 - metabolism / Interleukin-1beta - metabolism / Intracellular Signaling Peptides and Proteins - chemistry / Lipids / Lysis / Macrophages / Macrophages - metabolism / Mice / Mice, Inbred C57BL / Microscopy / multidisciplinary / Mutation / Organelles / Phosphate-Binding Proteins - chemistry / Physiological aspects / Pores / Precursors / Protein Precursors - metabolism / Protein Structure, Quaternary / Proteins / Science / Science (multidisciplinary) / Static Electricity / Structure