Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection

Abstract

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.

Deciphering the molecular nexus between Omicron infection and acute kidney injury: a bioinformatics approach

“…GBP1, through its GTPase activity, regulates cell death and has shown antiviral effects by promoting autophagy against pathogens ( Zhang et al, 2021 ; Zhu et al, 2024 ). TNFSF10’s (TRAIL) recognized role in apoptosis further highlights the importance of cell death regulation in the context of AKI and viral infections ( Dickinson et al, 2023 ), though its specific contributions require additional exploration.…”