Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection.
Shiwei ZhuClinton J BradfieldAgnieszka MaminskaEui-Soon ParkBae-Hoon KimPradeep KumarShuai HuangMinjeong KimYongdeng ZhangJoerg BewersdorfJohn D MacMickingPublished in: Science (New York, N.Y.) (2024)
All living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, large supramolecular complexes often activate immune proteins for protection. In this work, we resolved the native structure of a massive host-defense complex that polymerizes 30,000 guanylate-binding proteins (GBPs) over the surface of gram-negative bacteria inside human cells. Construction of this giant nanomachine took several minutes and remained stable for hours, required guanosine triphosphate hydrolysis, and recruited four GBPs plus caspase-4 and Gasdermin D as a cytokine and cell death immune signaling platform. Cryo-electron tomography suggests that GBP1 can adopt an extended conformation for bacterial membrane insertion to establish this platform, triggering lipopolysaccharide release that activated coassembled caspase-4. Our "open conformer" model provides a dynamic view into how the human GBP1 defense complex mobilizes innate immunity to infection.
Keyphrases
- cell death
- endothelial cells
- single cell
- induced pluripotent stem cells
- cell therapy
- pluripotent stem cells
- innate immune
- inflammatory response
- toll like receptor
- minimally invasive
- electron microscopy
- stem cells
- oxidative stress
- molecular dynamics simulations
- mesenchymal stem cells
- cell proliferation
- signaling pathway
- multidrug resistant
- rare case
- endoplasmic reticulum stress
- solar cells