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A Bidirectional Regulatory ACLY-NLRP3 Axis Integrates Metabolic and Inflammatory Signaling to Control NLRP3 Inflammasome Activation

ABSTRACT:

The NLRP3 inflammasome is critical for host defense against bacterial infection and is involved in the pathogenesis of various inflammatory diseases. The aggregation of its sensor protein NLRP3 is a pivotal checkpoint for inflammasome activation. However, the regulatory mechanism of NLRP3 aggregation is not completely understood. Here, we identify the metabolic enzyme ATP-citrate lyase (ACLY) as a direct binding partner that constrains NLRP3 aggregation, membrane translocation and activation. We demonstrate that ACLY interacts with the NLRP3-PYD independently of its enzymatic function, thereby sterically hindering NLRP3 aggregation and suppressing inflammasome assembly. Paradoxically, we find that NLRP3 binding to ACLY inhibits ACLY’s enzymatic activity and remodels cellular metabolism, which counteracts the stimulatory effect of ACLY on NLRP3 inflammasome activation. This reciprocal interaction reveals an essential role of ACLY as a brake for NLRP3 aggregation, and also establishes NLRP3 as a metabolic checkpoint to regulate ACLY-mediated metabolism. Furthermore, we develop a peptide that disrupts the ACLY-NLRP3 interaction and promotes NLRP3 inflammasome activation, which enhances host defense against bacterial infection. Our work delineates a self-limiting circuit for immunometabolic crosstalk, positioning the ACLY-NLRP3 axis as a new therapeutic target for inflammasome-driven pathologies.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13400 | MetaboLights | 2026-01-07

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13400_LC-MS_alternating_reverse-phase_metabolite_profiling-1.txt	Txt
	a_MTBLS13400_LC-MS_positive_hilic_metabolite_profiling-1.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13400_LC-MS_alternating_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13400_LC-MS_positive_hilic_metabolite_profiling-1_v2_maf.tsv	Tabular

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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A Bidirectional Regulatory ACLY-NLRP3 Axis Integrates Metabolic and Inflammatory Signaling to Control NLRP3 Inflammasome Activation

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