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Talk by Miriam Kutsch

Title: "Stick it together and break it down: how GBP1 fulfills antibacterial functions"
Occasion: SFB - Seminar
Start: 14.12.2023 - 16:15
Location: CellNanOs, 38/201

About the speaker: Jun.-Prof. Dr. Miriam Kutsch conducts research about molecular pathogenity at the Heinrich Heine University Düsseldorf.

Abstract of the talk: Gram-negative bacterial pathogens are protected from antimicrobials by surface exposed lipopolysaccharide (LPS), the main building block of the outer membrane. Besides transforming the bacterial envelope into an effective permeability barrier, LPS is also a potent inducer of innate immunity. Interferon-inducible guanylate-binding proteins (GBPs) are key players of innate immunity and promote host defense against cytosol invading Gram-negatives by facilitating bacterial lysis and caspase-4 initiated pyroptosis. The molecular mechanisms underlying these antibacterial functions were elusive. Our cell-free and cell-based studies identified GBP1 as novel LPS sensor that targets cytosolic bacteria directly to form an antimicrobial protein coat. This GBP1 microcapsule breaks down the protective outer membrane barrier for antimicrobial recognition and killing. Our work further shows that binding to intracellular bacteria is dispensable for GBPs to promote inflammatory cell death thereby rejecting the prevailing model that GBPs build a platform on the bacterial surface to activate the non-canonical inflammasome caspase-4. We demonstrate that detergent-like GBP1 and GBP2 form GBP-LPS complexes which are sufficient to enhance activation of caspase-4 in a cell-free in vitro system. Identifying GBP1 as LPS surfactant that breaks down the outer membrane barrier for antimicrobials and revealing that GBP1 and GBP2 assemble cytosol contaminating LPS into a hub for non-canonical inflammasome activation provide a novel mechanistic framework for how GBPs take part in the coordinated host response to Gram-negative bacterial infections.