AIM2 contributes to the maintenance of intestinal integrity via Akt and protects against Salmonella mucosal infection

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Guanylate-binding proteins promote AIM2 inflammasome activation during Francisella novicida infection by inducing cytosolic bacteriolysis and DNA release

Etienne Meunier, Pierre Wallet, Roland F. Dreier … (2015)

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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The transcription factor IRF1 and guanylate-binding proteins target AIM2 inflammasome activation by Francisella infection

Si Man, Rajendra Karki, R.K. Subbarao Malireddi … (2015)

Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms controlling activation of the AIM2 inflammasome in response to different cytosolic pathogens is unclear. Here, we show that the transcription factor IRF1 is the upstream molecule leading to AIM2 inflammasome activation during Francisella novicida infection, whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus or transfected dsDNA did not require IRF1. F. novicida infection detected by the cGAS-STING pathway induces type I interferon-dependent expression of IRF1, which drives the expression of guanylate-binding proteins (GBPs) leading to intracellular bacterial killing and DNA release. These results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell.

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Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt.

Justin E. Wilson, Alex Petrucelli, Liang Chen … (2015)

The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.