Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kutsch, M; Sistemich, L; Lesser, CF; Goldberg, MB; Herrmann, C; Coers, J

Published Date

  • July 1, 2020

Published In

Volume / Issue

  • 39 / 13

Start / End Page

  • e104926 -

PubMed ID

  • 32510692

Pubmed Central ID

  • PMC7327485

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

Digital Object Identifier (DOI)

  • 10.15252/embj.2020104926


  • eng

Conference Location

  • England