biostudies-literatureLi Xthe Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College, Soochow UniversityOpen Program of the State key Laboratroy of Radiation Medicine and ProtectionMOST | National Natural Science Foundation of China (NSFC)MOST | | Medical Science and Technology Project of Zhejiang Province ( )MOST | 浙 江 省 卫 生 厅 | Medical Science and Technology Project of Zhejiang ProvinceMOST | National Natural Science Foundation of China4954-4983https://www.ebi.ac.uk/biostudies/studies/S-EPMC11535217biostudies-literatureUnknown43(21)Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with eleThe EMBO journalAcetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis.PMC115352172024KY670GZK12023025YXY2304036820300778182010802381929132018YFC1705505Zhang FFan WDu JKShao JTao HDeng JJin YChinn YECheng XHuang PYue JYe MLi XShao ZShao YZhou CChen YKong YWu XfalseAcetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis.Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with ele2024-01-01T00:00:00Z2024 Nov2026-06-01T20:31:38.173Z2025-04-04T11:43:01.926ZS-EPMC115352173929447310.1038/s44318-024-00237-8