Ask about this productRelated genes to: PPT1 antibody
- Gene:
- PPT1 NIH gene
- Name:
- palmitoyl-protein thioesterase 1
- Previous symbol:
- PPT
- Synonyms:
- CLN1, INCL
- Chromosome:
- 1p34.2
- Locus Type:
- gene with protein product
- Date approved:
- 2000-06-09
- Date modifiied:
- 2019-04-23
Related products to: PPT1 antibody
Related articles to: PPT1 antibody
- Palmitoylation is a reversible lipid modification, regulating protein localization and signaling in neurons. Growth-associated protein 43 (GAP43) requires palmitoylation for axonal development and synaptic plasticity; however, its depalmitoylase and regulation in neural circuits remain unknown. We investigated whether palmitoyl-protein thioesterase 1 (PPT1) is the principal depalmitoylase for GAP43 and examined how disrupted PPT1-GAP43 signaling affects neuronal morphology and circuit function. Using biochemical assays, structural modeling, CRISPR-Cas9-generated GAP43 point mutation mice (GAP43-PM), PPT1-knockout mice (PPT1-KO), electrophysiology, and behavior, we demonstrated that PPT1 interacts with GAP43 at Cys and Cys to mediate its depalmitoylation, disruption of this interaction causes GAP43 hyperpalmitoylation that drove excessive dendritic arborization and aberrant growth cone expansion, enhanced glutamatergic transmission, and hippocampal network hyperexcitability, resulting in cognitive deficits without lysosomal storage pathology. Exogenous PPT1 reduced these morphological/synaptic abnormalities. Our findings establish the PPT1-GAP43 depalmitoylation pathway as essential for neuronal circuit homeostasis; its dysfunction contributes to neurodevelopmental disorders, identifying a potential therapeutic target for palmitoylation-related neurodevelopmental disorders. - Source: PubMed
Publication date: 2026/05/13
Tong JiaLiu YangWu WanliuWang QianqianYang HuifangLi JunyaoGao ZiyanLiu WeizhenLiu JieChazot PaulLu LiaoxunLiang YinmingLu Chengbiao - While osteoporosis (OP) affects over 200 million people globally, the causal roles of protein palmitoylation and its upstream epigenetic regulation in the pathogenesis of the disease remain undefined. We aimed to investigate whether DNA methylation causally influences OP risk by modulating the expression of palmitoylation-related genes. We employed an integrated multi-omics causal inference framework, combining 2-sample Mendelian randomization (MR), summary-data-based MR, Bayesian colocalization, and 2-step mediation MR analyses. Data were sourced from large-scale consortia: the FinnGen study (genome-wide association study: 10,461 cases, 473,264 controls), eQTLGen, GTEx (expression quantitative trait loci), and the GoDMC database (methylation quantitative trait loci). Two-sample MR identified ZDHHC5 as a protective factor (odds ratio = 0.81, 95% confidence interval: 0.76-0.87; P = 6.8 × 10-9) and the depalmitoylase PPT1 as a risk factor (odds ratio = 1.06, 95% confidence interval: 1.03-1.08; P = 7.9 × 10-5) for OP. These findings were corroborated by summary-data-based analysis, and colocalization confirmed a shared causal variant at the ZDHHC5 locus (posterior probability of H4 = 0.947). Mediation analysis revealed that DNA methylation is a central mechanistic link: methylation at site cg13473383 mediated 92.7% of ZDHHC5's protective effect, while sites cg04560534 and cg07033722 mediated 74.8% and 43.4%, respectively, of PPT1's risk effect. This study is the first to establish a causal epigenetic-palmitoylation axis in OP. The genes ZDHHC5 and PPT1, regulated by specific DNA methylation sites, represent novel potential therapeutic targets and biomarkers, offering fresh insights for precision medicine strategies against bone loss. - Source: PubMed
Wang ChaoZhu YongRuan Zhe - Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of lipofuscin in the aged and CLN1 brain to be remarkably similar. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, > 95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration. - Source: PubMed
Publication date: 2026/05/03
Tieze Sofia MassaroEsqueda AlexanderMcAllister RachelLagator MatijaYücel BetülSun EricHenke Katherine BLam TuKiet TLockyer NicholasGupta KallolChandra Sreeganga S - Osteosarcoma (OS) is characterized by high malignancy and profound metabolic reprogramming, yet the upstream regulators of its lipid metabolic adaptations remain largely elusive. Here, we report that RHBDL2 is significantly overexpressed in OS tissues, correlating with advanced clinical stage and poor patient prognosis. Mechanistically, multi-omics and structural analyses reveal that RHBDL2 functions as a non-proteolytic scaffold to stabilize the deubiquitinase USP3. This interaction is mediated by a compact hydrophobic core anchored by the Val245 residue of RHBDL2 and occurs independently of its protease activity. Stabilized USP3 subsequently prevents the proteasomal degradation of Palmitoyl-Protein Thioesterase 1 (PPT1) through deubiquitination. We further identify PPT1 as a metabolic rheostat that fuels OS malignancy by orchestrating FASN-dependent de novo lipogenesis, a requirement that can be partially bypassed by exogenous lipid supplementation. This RHBDL2-USP3-PPT1 axis promotes OS cell proliferation, migration, and epithelial-mesenchymal transition while suppressing apoptosis. Pharmacological screening identified Epigallocatechin gallate (EGCG) as a potent inhibitor that competitively disrupts the RHBDL2-USP3 interaction interface, thereby suppressing the downstream lipogenic program and inhibiting tumor growth and bone destruction in vivo. Collectively, our findings delineate a novel signaling cascade linking post-translational protein stabilization to metabolic adaptation, highlighting the RHBDL2-USP3 structural interface as a promising therapeutic vulnerability in osteosarcoma. - Source: PubMed
Publication date: 2026/04/24
Fan LiTao ChengZeng XiangweiLiu JianpengCao RuboZhu Kewei - While immunometabolic crosstalk is critical for antiviral defence, the regulation of this process, particularly through post-translational modifications, remains incompletely understood. How specific metabolites and associated modifications orchestrate antiviral immunity remains unclear. By screening a metabolic chemical library, we identify palmitic acid (PA) as an activator of antiviral immunity in macrophages. PA induces UMP-CMP kinase 2 (CMPK2) palmitoylation, maintaining its mitochondrial localization. CMPK2 is vital for the production of 3'-deoxy-3',4',-didehydrocytidine triphosphate (ddhCTP) and the stabilization of mitochondrial antiviral signaling protein (MAVS), both of which are crucial for defence against RNA viruses. Cmpk2 deficiency impairs IFN-I production and increases viral replication. Furthermore, the palmitoyl transferase ZDHHC20 catalyzes CMPK2 palmitoylation at cysteines 137 and 153, which are depalmitoylated by the thioesterase PPT1. PPT1 deficiency restores CMPK2 palmitoylation and antiviral immunity. Both a palm oil-rich diet and the in vivo administration of the PPT1 inhibitor DC661 increase IFN-I production. Therefore, the PA-ZDHHC20-CMPK2-PPT1 axis enhances the antiviral response, indicating that targeting PPT1 has the potential to treat RNA virus infections. - Source: PubMed
Publication date: 2026/04/21
Wang YujiaCui ZenghuiZhang YunkaiLi ZhiqingCao Xuetao