Cryo-ET of a human GBP coatomer governing cell-autonomous innate immunity to infection

Abstract

All living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, these activities generate large supramolecular complexes that recruit immune proteins for protection. Here, we solve the native structure of a massive antimicrobial complex generated by polymerization of 30,000 human guanylate-binding proteins (GBPs) over the entire surface of virulent bacteria. Construction of this giant nanomachine takes [~]1-3 minutes, remains stable for hours, and acts as a cytokine and cell death signaling platform atop the coated bacterium. Cryo-ET of this "coatomer" revealed thousands of human GBP1 molecules undergo [~]260 [A] insertion into the bacterial outer membrane, triggering lipopolysaccharide release that activates co-assembled caspase-4. Together, our results provide a quasi-atomic view of how the GBP coatomer mobilizes cytosolic immunity to combat infection in humans. One-Sentence SummaryThousands of GBPs coat cytosolic bacteria to engineer an antimicrobial signaling platform inside human cells.