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

ABSTRACT: The inflammasome activates caspase-1 and the release of interleukin-1? (IL-1?) 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-1? 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.

SUBMITTER: Wilson JE

PROVIDER: S-EPMC4529369 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Wilson Justin E JE Petrucelli Alex S AS Chen Liang L Koblansky A Alicia AA Truax Agnieszka D AD Oyama Yoshitaka Y Rogers Arlin B AB Brickey W June WJ Wang Yuli Y Schneider Monika M Mühlbauer Marcus M Chou Wei-Chun WC Barker Brianne R BR Jobin Christian C Allbritton Nancy L NL Ramsden Dale A DA Davis Beckley K BK Ting Jenny P Y JP

Nature medicine 20150624 8

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-defic ...[more]

PMID: 26107252

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Project description:Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2-/- mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2-/- mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2-/- mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2-/- mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2-/- mice. Furthermore, the reduction in apoptosis is observed in Aim2-/- mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2-/- mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections.

Project description:AIM2, a cytosolic DNA sensor, plays an important role during infection caused by pathogens with double-stranded DNA; however, its role in human cytomegalovirus (HCMV) infection remains unclear. Previously, we showed an increase in AIM2 protein levels during the early stage of HCMV infection and a decrease 24 h post infection. Because HCMV has developed a variety of strategies to evade host immunity, we speculated that this decline might be attributed to a viral immune escape mechanism. The tegument protein pUL83 is an important immune evasion protein and several studies have reported that pUL83 binds to specific cellular proteins, such as AIM2-like receptor IFI16, to affect their functions. To determine whether pUL83 contributes to the variation in AIM2 levels during HCMV infection, we investigated the pUL83/AIM2 interaction and its impact on the AIM2 inflammasome activation.We constructed plasmids expressing recombinant pUL83 and AIM2 proteins for two-hybrid and chemiluminescence assays. Using co-immunoprecipitation and immunofluorescent co-localization, we confirmed the interaction of pUL83/AIM2 in THP-1-derived macrophages infected with HCMV AD169 strain. Furthermore, by investigating the expression and cleavage of inflammasome-associated proteins in recombinant HEK293T cells expressing AIM2, apoptosis-associated speck-like protein (ASC), pro-caspase-1 and pro-IL-1?, we evaluated the effect of pUL83 on the AIM2 inflammasome.An interaction between pUL83 and AIM2 was detected in macrophages infected with HCMV as well as in transfected HEK293T cells. Moreover, transfection of the pUL83 expression vector into recombinant HEK293T cells stimulated by poly(dA:dT) resulted in reduced expression and activation of AIM2 inflammasome-associated proteins, compared with the absence of pUL83.Our data indicate that pUL83 interacts with AIM2 in the cytoplasm during the early stages of HCMV infection. The pUL83/AIM2 interaction deregulates the activation of AIM2 inflammasome. These findings reveal a new strategy of immune evasion developed by HCMV, which may facilitate latent infection.

Dataset Information

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

Publications

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

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