Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection
Shiwei Zhu, Clinton J. Bradfield, Agnieszka Mamińska, Eui‐Soon Park, Bae-Hoon Kim, Pradeep Kumar, Shuai Huang, Minjeong Kim, Yongdeng Zhang, Joerg Bewersdorf, John D. MacMicking
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.