Dataset Information

ITRAQ-based MS analysis of nasopharyngeal carcinoma cells with inflammasome activation

ABSTRACT: We previously reported that tumor-cell inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable ASC specks and govern the cellular secretion of IL-1. However, we know little about the biological and biochemical differences between cells with and without ASC speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients with [Define this term?] high-NLRP3 tumors, better recurrence-free survival was significantly associated with high-level expression of NDUFB8 (P=0.037) and ATP5B (P=0.029), as examined using immunohistochemistry. Together, our results demonstrate that upregulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be prognostic markers and/or promising therapeutic targets in patients with NPC.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Chih-Ching Wu

LAB HEAD: Chih-Ching Wu

PROVIDER: PXD013071 | Pride | 2019-11-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20161228-iTQ-HWC-20ug-s01.raw	Raw
	20161228-iTQ-HWC-20ug-s02.raw	Raw
	20161228-iTQ-HWC-20ug-s03.raw	Raw
	20161228-iTQ-HWC-20ug-s04.raw	Raw
	20161228-iTQ-HWC-20ug-s05.raw	Raw

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Publications

Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma.

Chung I-Che IC Chen Lih-Chyang LC Tsang Ngan-Ming NM Chuang Wen-Yu WY Liao Tzu-Chieh TC Yuan Sheng-Ning SN OuYang Chun-Nan CN Ojcius David M DM Wu Chih-Ching CC Chang Yu-Sun YS

Molecular & cellular proteomics : MCP 20191113 1

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1β. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteom ...[more]

PMID: 31723016

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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.