PCK2-Mediated PQBP1 Lactylation Promotes Asthmatic Inflammation through PRMT5 Inhibition
Qiaoyun Bai1,2, Ningpo Ding1,2, Rixin Feng1,2
1Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, P.R. China.
Abstract:
Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through posttranslational modifications remains unclear. Methods: We used house dust mite (HDM)-induced asthmatic mice with multiomics analyses (metabolomics, posttranslational modification-proteomics, and chromatin immunoprecipitation sequencing) and validated findings through gene editing and adeno-associated virus interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. Phosphoenolpyruvate carboxykinase 2 (PCK2) succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered polyglutamine-binding protein 1 (PQBP1) lactylation at K223, enabling protein arginine methyltransferase 5 (PRMT5)/WD repeat domain 77 complex inhibition. This erased H4R3me2s repressive marks from proinflammatory gene promoters, particularly mitogen-activated protein kinase pathway genes, causing transcriptional derepression. Airway epithelium-specific Pqbp1 knockout reduced inflammation, goblet cell hyperplasia, and T helper 2 responses. Pck2-short hairpin RNA or oxamate treatment ameliorated asthmatic pathology. Conclusion: We identified a PCK2-lactate-PQBP1-PRMT5 axis linking metabolic reprogramming to epigenetic dysregulation in asthma. PCK2-K100 succinylation drives lactate accumulation, inducing PQBP1-K223 lactylation that inhibits PRMT5 and activates inflammatory genes, representing a therapeutic target for asthma.
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