PXD014828

PXD014828 is an original dataset announced via ProteomeXchange.

Title	DDX3X Acts as a Live or Die Checkpoint in Stressed Cells by Regulating NLRP3 Inflammasome
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:57:29.748.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thirumala-Devi Kanneganti
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	N-ethylmaleimide derivatized cysteine; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-30 05:51:23	ID requested
1	2019-10-03 04:41:46	announced
⏵ 2	2024-10-22 04:57:35	announced	2024-10-22: Updated project metadata.

Samir P, Kesavardhana S, Patmore DM, Gingras S, Malireddi RKS, Karki R, Guy CS, Briard B, Place DE, Bhattacharya A, Sharma BR, Nourse A, King SV, Pitre A, Burton AR, Pelletier S, Gilbertson RJ, Kanneganti TD, DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature, 573(7775):590-594(2019) [pubmed]

10.1038/s41586-019-1551-2;

submitter keyword: IL-18, caspase-1, DDX3X, inflammasome, proinflammatory cytokines, pyroptosis,stress granules, IL-1β, cytoplasmic compartments, ASC specks, NLRP3

Thirumala-Devi Kanneganti
contact affiliation	Department of Immunology, St. Jude Children's Research Hospital
contact email	thirumala-devi.kanneganti@stjude.org
lab head
Thirumala-Devi Kanneganti
contact affiliation	St. Jude Children's Research Hospital
contact email	thirumala-devi.kanneganti@stjude.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014828
     1. Label: PRIDE project
     2. Name: DDX3X Acts as a Live or Die Checkpoint in Stressed Cells by Regulating NLRP3 Inflammasome