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

Abstract Emerging evidence indicates that the accumulated D-lactate (D-la) from intestinal bacteria induces diverse effects in human intestinal injury diseases. However, its regulatory mechanism and functional consequence remain unclear. Here, we show that the secreted D-la induces lysine D-lactylation (K-Dla) to modulate transcription in host cells. We uncover K-Dla in HepG2 cells stimulated by D-la from E. coli secretions. Then, we confirm the occurrence of D-la-driven K-Dla by four orthogonal approaches. We further validate that the existence of K-Dla in organisms by detecting the mouse liver and human intestinal tissue. Besides, we demonstrate a SCOT1-catalyzed biosynthetic pathway of D-lactyl-CoA, serving as a key donor for K-Dla. Next, we identify the K-Dla landscape with 2895 sites and further suggest the regulation of histone K-Dla in transcription by MNase ChIP-seq and RNA-seq assays. Finally, we show the potential effect of K-Dla on inhibiting the hepatocellular carcinoma cell proliferation. In summary, we report that the secreted D-la can induce K-Dla to regulate transcription, providing a new insight into the function of D-la secreted by gut microbiota and the effect of protein chemical modifications induced by bacterial secretions.