Toll-like receptor (TLR)/myeloid differentiation primary response protein (MYD88) signaling aggravates sepsis by impairing neutrophil migration to infection sites. However, the role of intracellular fatty acids in TLR/MYD88 signaling is unclear. Here, inhibition of fatty acid synthase by C75 improved neutrophil chemotaxis and increased the survival of mice with sepsis in cecal ligation puncture and lipopolysaccharide-induced septic shock models. C75 specifically blocked TLR/MYD88 signaling in neutrophils. Treatment with GSK2194069 that targets a different domain of fatty acid synthase, did not block TLR signaling or MYD88 palmitoylation. De novo fatty acid synthesis and CD36-mediated exogenous fatty acid incorporation contributed to MYD88 palmitoylation. The binding of IRAK4 to the MYD88 intermediate domain and downstream signal activation required MYD88 palmitoylation at cysteine 113. MYD88 was palmitoylated by ZDHHC6, and ZDHHC6 knockdown decreased MYD88 palmitoylation and TLR/MYD88 activation upon lipopolysaccharide stimulus. Thus, intracellular saturated fatty acid-dependent palmitoylation of MYD88 by ZDHHC6 is a therapeutic target of sepsis.
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Any Supplementary information, chemical compound information are available in the online version of the paper. The data that support the findings of this study are available from the corresponding author upon request.
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We thank M.A. Farrar (Univ. of Minnesota) for the pKS-GyrB construct; M. Fukata (National Institute for Physiological Science and National Institutes of Natural Sciences) for the 24 pEF-Bos-zDHHC-HA constructs. This study was supported by grants from the Korea Health Technology R&D Project ‘Strategic Center of Cell and Bio Therapy’ (grant no. HI17C2085; H.-S.K.) and ‘Korea Research-Driven Hospital’ (grant no. HI14C1277; H.-S.K.) through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Korea and from the National Research Foundation of Korea funded by the Korea Government (grant no. 2018R1C1B5086482; S.E.L.).
The authors declare no competing interests.
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Kim, YC., Lee, S.E., Kim, S.K. et al. Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation. Nat Chem Biol 15, 907–916 (2019). https://doi.org/10.1038/s41589-019-0344-0
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