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Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions
Author(s) -
Kutsch Miriam,
Sistemich Linda,
Lesser Cammie F,
Goldberg Marcia B,
Herrmann Christian,
Coers Jörn
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104926
Subject(s) - biology , bacteria , microbiology and biotechnology , genetics
In the outer membrane of gram‐negative bacteria, O‐antigen segments of lipopolysaccharide (LPS) form a chemomechanical barrier, whereas lipid A moieties anchor LPS molecules. Upon infection, human guanylate binding protein‐1 (hGBP1) colocalizes with intracellular gram‐negative bacterial pathogens, facilitates bacterial killing, promotes activation of the lipid A sensor caspase‐4, and blocks actin‐driven dissemination of the enteric pathogen Shigella . The underlying molecular mechanism for hGBP1's diverse antimicrobial functions is unknown. Here, we demonstrate that hGBP1 binds directly to LPS and induces “detergent‐like” LPS clustering through protein polymerization. Binding of polymerizing hGBP1 to the bacterial surface disrupts the O‐antigen barrier, thereby unmasking lipid A, eliciting caspase‐4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the function of the Shigella outer membrane actin motility factor IcsA. These findings characterize hGBP1 as an LPS‐binding surfactant that destabilizes the rigidity of the outer membrane to exert pleiotropic effects on the functionality of gram‐negative bacterial cell envelopes.