A hierarchical GBP network promotes cytosolic LPS recognition and sepsis
Abstract Bacterial lipopolysaccharide (LPS) is one of the most bioactive substances known. Trace amounts trigger robust immunity to infection but also life-threatening sepsis causing millions of deaths each year. LPS contamination of the cytosol elicits a caspase-dependent inflammasome pathway promoting cytokine release and host cell death. Here, we report an immune GTPase network controls multiple steps in this pathway by genome-engineering mice to lack 7 different guanylate-binding proteins (GBPs). Gbp2-/- and Gbp3-/- mice had severe caspase-11-driven defects that protected them from septic shock. Gbp2 recruited caspase-11 for LPS recognition whereas Gbp3 assembled and trafficked the pyroptotic pore-forming protein, gasdermin D, after caspase-11 cleavage. Together, our results identify a new functional hierarchy wherein different GBPs choreograph sequential steps in the non-canonical inflammasome pathway to control Gram-negative sepsis.One-Sentence Summary Immune GTPase network orchestrates hierarchical immunity to bacterial products in vivo.
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 28. Aug. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Park, Eui-Soon [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.08.25.457662 |
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| funding: |
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| PPN (Katalog-ID): |
XBI032466676 |
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| 245 | 1 | 0 | |a A hierarchical GBP network promotes cytosolic LPS recognition and sepsis |
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| 520 | |a Abstract Bacterial lipopolysaccharide (LPS) is one of the most bioactive substances known. Trace amounts trigger robust immunity to infection but also life-threatening sepsis causing millions of deaths each year. LPS contamination of the cytosol elicits a caspase-dependent inflammasome pathway promoting cytokine release and host cell death. Here, we report an immune GTPase network controls multiple steps in this pathway by genome-engineering mice to lack 7 different guanylate-binding proteins (GBPs). Gbp2-/- and Gbp3-/- mice had severe caspase-11-driven defects that protected them from septic shock. Gbp2 recruited caspase-11 for LPS recognition whereas Gbp3 assembled and trafficked the pyroptotic pore-forming protein, gasdermin D, after caspase-11 cleavage. Together, our results identify a new functional hierarchy wherein different GBPs choreograph sequential steps in the non-canonical inflammasome pathway to control Gram-negative sepsis.One-Sentence Summary Immune GTPase network orchestrates hierarchical immunity to bacterial products in vivo | ||
| 700 | 1 | |a Kim, Bae-Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Pradeep |e verfasserin |4 aut | |
| 700 | 1 | |a Tretina, Kyle |e verfasserin |4 aut | |
| 700 | 1 | |a Maminska, Agnieszka |e verfasserin |4 aut | |
| 700 | 1 | |a Philbrick, William M. |e verfasserin |4 aut | |
| 700 | 1 | |a Flavell, Richard A. |e verfasserin |4 aut | |
| 700 | 1 | |a MacMicking, John D. |e verfasserin |4 aut | |
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