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Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation

Kim, Young-Chan, Lee, Sang Eun, Kim, Somi K., Jang, Hyun-Duk, Hwang, Injoo, Jin, Sooryeonhwa, Hong, Eun-Byeol, Jang, Kyoung-Soon, Kim, Hyo-Soo·2019·Nature Chemical Biology
DOI 10.1038/s41589-019-0344-0
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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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Metadata

Authors
Kim, Y.-C., Lee, S. E., Kim, S. K., Jang, H.-D., Hwang, I., Jin, S., Hong, E.-B., Jang, K.-S., & Kim, H.-S.
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2019-08-19
Volume
15
Issue
9
Pages
907-916
ISSN
  • 1552-4450
  • 1552-4469
DOI
10.1038/s41589-019-0344-0
Cited by
184
References
6
Language
en
Licence
Funders
  • National Research Foundation of Korea (2018R1C1B5086482)
  • Korea Health Industry Development Institute (HI14C1277, HI17C2085)

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