Guanylate-binding proteins promote AIM2 inflammasome activation during Francisella novicida infection by inducing cytosolic bacteriolysis and DNA release
The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines IL-1β and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella novicida...
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Veröffentlicht in: | Nature immunology 2015-03, Vol.16 (5), p.476-484 |
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Hauptverfasser: | , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines IL-1β and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as
Francisella novicida.
AIM2 activation by
F. novicida
requires bacteriolysis, yet whether this process is accidental or a host-driven immune mechanism remained unclear. Using siRNA screening for nearly 500 interferon-stimulated genes, we identified guanylate-binding proteins GBP2 and GBP5 as key AIM2 activators during
F. novicida
infection. Their prominent role was validated
in vitro
and in a mouse model of tularemia. Mechanistically, these two GBPs target cytosolic
F. novicida
and promote bacteriolysis. Thus, besides their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria. |
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ISSN: | 1529-2908 1529-2916 |
DOI: | 10.1038/ni.3119 |