PCK2-mediated PQBP1 lactylation promotes asthmatic inflammation through PRMT5 inhibition

ABSTRACT: Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through post-translational modifications remains unclear. Methods: We used HDM-induced asthmatic mice with multi-omics analyses (metabolomics, PTM-proteomics, ChIP-seq) and validated findings through gene editing and AAV interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. PCK2 succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered PQBP1 lactylation at K223, enabling PRMT5/WDR77 complex inhibition. This erased H4R3me2s repressive marks from pro-inflammatory gene promoters, particularly MAPK pathway genes, causing transcriptional de-repression. Airway epithelium-specific PQBP1 knockout reduced inflammation, goblet cell hyperplasia, and Th2 responses. PCK2-shRNA 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Guanghai Yan  

PROVIDER: PXD070618 | iProX | Wed Nov 12 00:00:00 GMT 2025

REPOSITORIES: iProX