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


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.

SUBMITTER: Santos JC 

PROVIDER: S-EPMC7314798 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Santos José Carlos JC   Boucher Dave D   Schneider Larisa Kapinos LK   Demarco Benjamin B   Dilucca Marisa M   Shkarina Kateryna K   Heilig Rosalie R   Chen Kaiwen W KW   Lim Roderick Y H RYH   Broz Petr P  

Nature communications 20200624 1


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 associat  ...[more]

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