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D-lactate derived from bacteria drives lysine D-lactylation to modulate transcription in liver cells

ABSTRACT: Emerging evidence suggests that accumulated D-lactate (D-la) induces diverse effects in human intestinal injury diseases. However, the regulatory mechanism remain elusive. Here, we discover the lysine D-lactylation (D-Kla) induced by D-la and reveal the molecular mechanism underlying D-la-driven D-Kla for transcription regulation. We first discovered D-Kla in HepG2 cells stimulated by D-la from E. coli secretions. Next, we validated the existence of D-la-driven D-Kla by four approaches, especially including metabolic labelling experiments. Additionally, we uncover that SCOT1 catalyzes the transformation of D-la to D-lactyl-CoA, serving as a key donor for D-Kla. Furthermore, we identify the D-Kla landscape with 2895 sites by proteomics analysis and 34 histone D-Kla sites activated by D-la and further indicate the regulation of H3K18-Dla in transcription by CUT&Tag and RNA-seq assays. Finally, we show the effect of D-Kla on inhibiting the hepatocellular carcinoma cells proliferation. In summary, we uncover the D-la-driven D-Kla and reveal a D-Kla-mediated transcription regulation for tumor suppression, providing new insight into the protein modifications induced by microbiota secretions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269963 | GEO | 2026/07/15

REPOSITORIES: GEO

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