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.
Highlights
The human non-canonical inflammasome controls caspase-4 activation and gasdermin-Ddependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS)
We show that human GBP1 targets cytosolic Salmonella seconds after the bacteria escape from the vacuole and enter into the cytosol, and that GBP1 initiates the hierarchical recruitment of GBP2-4 and the assembly of a guanylate-binding proteins (GBPs) coat on cytosolic bacteria
Since HeLa cells express Toll-like receptor 4 (TLR4) but not MD-2 and are not responsive to extracellular bacterial LPS16, we primed the cells with IFNγ, a cytokine that plays a critical role in intestinal immunity against Salmonella[17]
Summary
The human non-canonical inflammasome controls caspase-4 activation and gasdermin-Ddependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Caspase-11 activation in mouse macrophages transfected with LPS or infected with Gram-negative bacteria requires the expression of interferon (IFN)-inducible GTPases, which include the GBPs (guanylate-binding proteins) or IRGs (immunity-related GTPases)[9,10,11,12]. These GTPases are highly upregulated after type-I or type-II IFN priming, and essential for cell-autonomous immunity against a variety of viruses, bacteria and parasites[13]. We show that GBP1 acts as a bona-fide cytosolic LPS sensor that detects and targets the LPS-containing membranes of Gram-negative bacteria, where it assembles a platform that promotes caspase-4 recruitment and activation
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