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Incoming poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human cells

ABSTRACT: The innate immune system recognizes cytosolic DNA as evidence of infection, although detailed analysis is mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used the inflammasome reporter caspase-1CARD-EGFP (C1C-EGFP) encoded in engineered viruses. We found that released genomes of the model poxvirus vaccinia virus (VACV) and monkeypox virus (MPXV) trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 PYD, most potently as bivalent nanobodies. Utilizing VACV expressing bivalent AIM2 nanobodies, we show that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans and provides the first evidence of cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Monocyte

SUBMITTER: Tabea Klein

LAB HEAD: Florian Schmidt

PROVIDER: PXD069678 | Pride | 2026-01-22

REPOSITORIES: Pride

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			Action	DRS
	20231215_E2_Neo_ColID_AUR04_25cm_TRAP_TK_AIM-2_IP_Round5_01.raw	Raw
	20231215_E2_Neo_ColID_AUR04_25cm_TRAP_TK_AIM-2_IP_Round5_02.raw	Raw
	20231215_E2_Neo_ColID_AUR04_25cm_TRAP_TK_AIM-2_IP_Round5_03.raw	Raw
	20231215_E2_Neo_ColID_AUR04_25cm_TRAP_TK_AIM-2_IP_Round5_04.raw	Raw
	20231215_E2_Neo_ColID_AUR04_25cm_TRAP_TK_AIM-2_IP_Round5_05.raw	Raw

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Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

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Incoming poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human cells

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