한빛사 논문
Young-Chan Kim1,2,7, Sang Eun Lee3,7, Somi K. Kim1,2,7, Hyun-Duk Jang1,2,7, Injoo Hwang1,2, Sooryeonhwa Jin1,2,4, Eun-Byeol Hong1,2, Kyoung-Soon Jang5 and Hyo-Soo Kim1,2,4,6*
1 Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, Seoul, Korea. 2 Korea Research-Driven Hospital, Seoul National University Hospital, Seoul, Korea. 3 Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 4 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea. 5 Biomedical Omics Center, Korea Basic Science Institute, Cheongju, South Korea. 6 World Class University Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea. 7 These authors contributed equally: Young-Chan Kim, Sang Eun Lee, Somi K. Kim, Hyun-Duk Jang.
*Correspondence to Hyo-Soo Kim
Abstract
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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