AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Micco, Antonia Di; Frera, Gianluca; Lugrin, Jérôme; Jamilloux, Yvan; Hsu, Erh-Ting; Tardivel, Aubry; Gassart, Aude De; Zaffalon, Léa; Bujisic, Bojan; Siegert, Stefanie; Quadroni, Manfredo; Brož, Petr; Henry, Thomas; Hrycyna, Christine A.; Martinon, Fabio

doi:10.1073/pnas.1602419113

Cited by 117 publications

(86 citation statements)

References 82 publications

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“…However, the secretion was unaffected when cells were transfected with poly (I:C) or infected with VSV-GFP or HSV-1-GFP (Fig 8). These results were generally in keeping with previous reports on the requirement of AIM2 for inflammasome activation induced by dsDNA, nelfinavir, and L. monocytogenes [8,9,12,17,51]. Also consistent with previous publications [3,9,51], silencing of endogenous IFI16-a only affected IL-1b secretion triggered by HSV-1 infection but not by other stimuli tested.…”

Section: Ifi16-b Inhibits Dsdna-induced Aim2 Inflammasome Activationsupporting

confidence: 93%

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Wang

Deng

et al. 2018

EMBO Reports

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Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-β, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-β contains two HIN domains, but lacks the pyrin domain. IFI16-β is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon-β or phorbol ester. IFI16-β co-localizes with AIM2 in the cytoplasm, whereas IFI16-α is predominantly found in the nucleus. IFI16-β interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-β sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-β inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-β augments interleukin-1β secretion triggered by dsDNA but not dsRNA Thus, cytoplasm-localized IFI16-β is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.

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Section: Ifi16-b Inhibits Dsdna-induced Aim2 Inflammasome Activationsupporting

confidence: 93%

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Wang

Deng

et al. 2018

EMBO Reports

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“…Cells forced through tiny pores exhibited cGAS localization at sites of NE ruptures indicating that cGAS is binding DNA at these sites . Participation of cytosolic innate immune receptors in NE‐stress and transient membrane rupture was recently confirmed in a model of pharmacological perturbation of the nuclear envelope structure . Lamin A maturation was found to be inhibited by the anti‐viral drug nelfinavir, causing pertubations in nuclear architecture and transient exchanges of nuclear and cytoplasmic contents.…”

Section: Aim2 Detection Of Dnamentioning

confidence: 94%

“…Lamin A maturation was found to be inhibited by the anti‐viral drug nelfinavir, causing pertubations in nuclear architecture and transient exchanges of nuclear and cytoplasmic contents. As consequence of exposure of nuclear DNA in the cytoplasm, AIM2 and cGAS cytosolic DNA sensors were activated (Figure ). These results further emphasized on a possible contribution of stress of the NE and its associated inflammatory pathways to diseases with transient NE ruptures, including laminopathies and cancers.…”

Section: Aim2 Detection Of Dnamentioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

Self Cite

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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“…The AIM2–ASC complex moves to the cytoplasm to assemble an inflammasome complex . Damage to the nuclear envelope caused by the HIV protease inhibitor Nelfinavir mediates the release of nuclear DNA . AIM2 is normally maintained in an autoinhibitory state via interaction between its HIN‐200 domain and the PYD .…”

Section: Aim2 Inflammasomementioning

confidence: 99%

Molecular mechanisms of inflammasome signaling

Mathur

Hayward

Man

2017

Journal of Leukocyte Biology

153

123

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The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1β and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.

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AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Cited by 117 publications

References 82 publications

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Molecular mechanisms of inflammasome signaling

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