LncRNA ZNF883-Mediated NLRP3 Inflammasome Activation and Epilepsy Development Involve USP47 Upregulation
Abstract
The goal of this study was to characterize the mechanisms of long noncoding RNA (lncRNA) ZNF883 regulating NOD-like receptor 3 (NLRP3) inflammasome activation in epilepsy (EP). Rat and cellular EP models were established using pilocarpine and magnesium-free extracellular fluid, respectively, to detect the differential expression of ZNF883, microRNA (miR)-138-5p, ubiquitin-specific peptidase 47 (USP47), and NLRP3. The pathology of the hippocampal neurons was examined by whole-cell patch clamping. The expression of ZNF883, miR-138-5p, and USP47 was modified in epileptic neurons, and the EP rats were injected with sh-ZNF883. Then, alterations in ZNF883, miR-138-5p, and USP47 levels were measured. The histopathology of the hippocampus was detected, along with the detection of IL-6, IL-1β, TNF-α, and NLRP3. Neuronal apoptosis in the rat and cellular EP models was determined. The relationship among ZNF883, miR-138-5p, and USP47 as well as the regulation of NLRP3 ubiquitination by USP47 was determined. ZNF883, USP47, and NLRP3 were increasingly expressed and miR-138-5p was downregulated in epileptic neurons and rats, concurrent with aggravated inflammation and apoptosis. ZNF883 overexpression in epileptic neurons elevated USP47 expression. ZNF883 targeted miR-138-5p and miR-138-5p negatively regulated USP47. In epileptic neurons, inhibiting miR-138-5p or overexpressing USP47 partially reversed the ZNF883 silencing-induced inhibition on NLRP3 inflammasome activation, neuronal apoptosis, and epileptiform activity. ZNF883 silencing in EP rats decreased USP47 and NLRP3, increased miR-138-5p, and inhibited inflammation and apoptosis. USP47 reversed the ubiquitination of NLRP3. ZNF883 inhibits NLRP3 ubiquitination and promotes EP through upregulating USP47 by sponging miR-138-5p.
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In autistic white Hispanics, almost 80% of males with epilepsy carried the rs2307073 synonymous variant within the epilepsy-associated USP47 host gene, compared to ~1/3rd of other autistic cases and 15% in the matched controls [F(1, 308) = 9.494, p = 0.002; post hoc: pTukey = 0.008-0.045] [31].
“In autistic white Hispanics, almost 80% of males with epilepsy carried the rs2307073 synonymous variant within the epilepsy-associated USP47 host gene, compared to ~1/3rd of other autistic cases and 15% in the matched controls [F(1, 308) = 9.494, p = 0.002; post hoc: pTukey = 0.008-0.045) [31].”
From Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings (2024) · cites this paper as [31]
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- Authors
- Gong, L., Han, Y., Chen, R., Yang, P., & Zhang, C.
- Affiliations
- Third Xiangya Hospital (CN)
- Corresponding author
- Zhang, Chen
- Venue
- Molecular Neurobiology
- Published
- 2022-06-09
- Volume
- 59
- Issue
- 8
- Pages
- 5207-5221
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W4281788844
- Cited by
- 26
- References
- 38
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 11 · 2023: 4 · 2022: 2
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- long non-coding RNA, NLRP3 inflammasome, USP47, miR-138-5p, epilepsy, neuroinflammation, neuronal apoptosis, hippocampal neurons, pilocarpine-induced epilepsy, epileptiform activity, IL-1β
- MeSH terms
- NLR Proteins, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Epilepsy, Inflammation, Up-Regulation, Apoptosis, MicroRNAs, Ubiquitin Thiolesterase, Rats, Inflammasomes, RNA, Long Noncoding, Ubiquitin-Specific Proteases
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