Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling

Shouya Feng, Daniel Enosi Tuipulotu, Abhimanu Pandey, Weidong Jing, Cheng Shen, Chinh Ngo, Melkamu B. Tessema, Fei-Ju Li, Daniel Fox, Anukriti Mathur, Anyang Zhao, Runli Wang, Klaus Pfeffer, Daniel Degrandi, Masahiro Yamamoto, Patrick C. Reading, Gaetan Burgio and Si Ming Man ()
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Shouya Feng: The Australian National University
Daniel Enosi Tuipulotu: The Australian National University
Abhimanu Pandey: The Australian National University
Weidong Jing: The Australian National University
Cheng Shen: The Australian National University
Chinh Ngo: The Australian National University
Melkamu B. Tessema: The University of Melbourne, The Peter Doherty Institute for Infection and Immunity
Fei-Ju Li: The Australian National University
Daniel Fox: The Australian National University
Anukriti Mathur: The Australian National University
Anyang Zhao: The Australian National University
Runli Wang: The Australian National University
Klaus Pfeffer: Heinrich-Heine-University Düsseldorf
Daniel Degrandi: Heinrich-Heine-University Düsseldorf
Masahiro Yamamoto: Osaka University
Patrick C. Reading: The University of Melbourne, The Peter Doherty Institute for Infection and Immunity
Gaetan Burgio: The Australian National University
Si Ming Man: The Australian National University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Inflammasomes are cytosolic signaling complexes capable of sensing microbial ligands to trigger inflammation and cell death responses. Here, we show that guanylate-binding proteins (GBPs) mediate pathogen-selective inflammasome activation. We show that mouse GBP1 and GBP3 are specifically required for inflammasome activation during infection with the cytosolic bacterium Francisella novicida. We show that the selectivity of mouse GBP1 and GBP3 derives from a region within the N-terminal domain containing charged and hydrophobic amino acids, which binds to and facilitates direct killing of F. novicida and Neisseria meningitidis, but not other bacteria or mammalian cells. This pathogen-selective recognition by this region of mouse GBP1 and GBP3 leads to pathogen membrane rupture and release of intracellular content for inflammasome sensing. Our results imply that GBPs discriminate between pathogens, confer activation of innate immunity, and provide a host-inspired roadmap for the design of synthetic antimicrobial peptides that may be of use against emerging and re-emerging pathogens.

Date: 2022
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DOI: 10.1038/s41467-022-32127-0

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