Journal
NATURE IMMUNOLOGY
Volume 16, Issue 5, Pages 476-U185Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3119
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Funding
- Swiss National Science Foundation [PP00P3_139120/1]
- University of Basel [ID2153162]
- European Research Council [311542]
- Deleguation Generale de l'Armement
- European Research Council (ERC) [311542] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [PP00P3_139120] Funding Source: Swiss National Science Foundation (SNF)
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The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1 beta (IL-1 beta) and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida (F. novicida). The activation of AIM2 by F. novicida requires bacteriolysis, yet whether this process is accidental or is a host-driven immunological mechanism has remained unclear. By screening nearly 500 interferon-stimulated genes (ISGs) through the use of small interfering RNA (siRNA), we identified guanylate-binding proteins GBP2 and GBP5 as key activators of AIM2 during infection with F. novicida. We confirmed their prominent role in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs targeted cytosolic F. novicida and promoted bacteriolysis. Thus, in addition to their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.
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