Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria

José Carlos Santos, Dave Boucher, Larisa Kapinos Schneider, Benjamin Demarco, Marisa Dilucca, Kateryna Shkarina, Rosalie Heilig, Kaiwen W. Chen, Roderick Y. H. Lim and Petr Broz ()
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José Carlos Santos: University of Lausanne
Dave Boucher: University of Lausanne
Larisa Kapinos Schneider: Biozentrum, University of Basel
Benjamin Demarco: University of Lausanne
Marisa Dilucca: University of Lausanne
Kateryna Shkarina: University of Lausanne
Rosalie Heilig: University of Lausanne
Kaiwen W. Chen: University of Lausanne
Roderick Y. H. Lim: Biozentrum, University of Basel
Petr Broz: University of Lausanne

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic Salmonella or upon cytosolic delivery of LPS. GBP1 associates with the surface of cytosolic Salmonella seconds after bacterial escape from their vacuole, initiating the recruitment of GBP2-4 to assemble a GBP coat. The GBP coat then promotes the recruitment of caspase-4 to the bacterial surface and caspase activation, in absence of bacteriolysis. Mechanistically, GBP1 binds LPS with high affinity through electrostatic interactions. Our findings indicate that in human epithelial cells GBP1 acts as a cytosolic LPS sensor and assembles a platform for caspase-4 recruitment and activation at LPS-containing membranes as the first step of non-canonical inflammasome signaling.

Date: 2020
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DOI: 10.1038/s41467-020-16889-z

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