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Stress granule phase separation in stress-responsive cytosolic extract-in-oil droplets

ABSTRACT: Stress granules (SGs) are biomolecular condensates that transiently form in the cytosol when cells are exposed to potentially hazardous conditions. Illustrating the physiological relevance of SGs, dysregulation of pathways leading to their assembly or disassembly is increasingly associated with human diseases related to ageing and neurodegeneration. In this study, we have devised a novel methodology for studying and manipulating SG phase separation in vitro, which offers a more sophisticated level of complexity. This innovative stress-responsive methodology empolyed emulsion-based droplet microfluidics to recreate an in vitro environment that resembles the confined active cytosolic milieu. After using different stress triggers, a condensate composition analysis by quantitative LC-MS/MS identified new SG client proteins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): U2-os Cell, Osteosarcoma Cell Line, Cell Culture

SUBMITTER: Pietro Scaturro

LAB HEAD: Pietro Scaturro

PROVIDER: PXD057906 | Pride | 2026-05-19

REPOSITORIES: pride

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			Action	DRS
	20211227_CF_HD202112_PEG_1_Slot1-42_1_2307.d.zip	Other
	20211227_CF_HD202112_PEG_2_Slot1-43_1_2308.d.zip	Other
	20211227_CF_HD202112_PEG_3_Slot1-44_1_2309.d.zip	Other
	20211227_CF_HD202112_PEG_4_Slot1-45_1_2310.d.zip	Other
	20211227_CF_HD202112_PEG_5_Slot1-46_1_2311.d.zip	Other

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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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Stress granule phase separation in stress-responsive cytosolic extract-in-oil droplets

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