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

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Toll-like receptor (TLR)/myeloid differentiation primary response protein (MYD88) signaling exacerbates sepsis by hindering neutrophil migration.
• The specific role of intracellular fatty acids in TLR/MYD88 signaling remains largely unknown.

Purpose of the Study:

• To investigate the role of intracellular fatty acids in TLR/MYD88 signaling during sepsis.
• To identify potential therapeutic targets within this pathway.

Main Methods:

• Utilized mouse models of sepsis (cecal ligation puncture and lipopolysaccharide-induced septic shock).
• Administered fatty acid synthase inhibitor C75 and a different fatty acid synthase domain inhibitor GSK2194069.
• Assessed neutrophil chemotaxis, survival rates, TLR/MYD88 signaling, and MYD88 palmitoylation.
• Investigated the contribution of de novo fatty acid synthesis and CD36-mediated uptake.
• Examined the role of ZDHHC6 in MYD88 palmitoylation via knockdown experiments.

Main Results:

• C75 treatment improved neutrophil chemotaxis and increased survival in sepsis models.
• C75 specifically inhibited TLR/MYD88 signaling in neutrophils, unlike GSK2194069.
• MYD88 palmitoylation, crucial for IRAK4 binding and downstream signaling, was dependent on intracellular saturated fatty acids.
• Both de novo synthesis and CD36-mediated uptake contributed to MYD88 palmitoylation.
• ZDHHC6 was identified as the enzyme responsible for MYD88 palmitoylation at cysteine 113.
• ZDHHC6 knockdown reduced MYD88 palmitoylation and TLR/MYD88 activation.

Conclusions:

• Intracellular saturated fatty acid-dependent palmitoylation of MYD88 by ZDHHC6 is a critical mediator of TLR/MYD88 signaling in sepsis.
• Targeting ZDHHC6-mediated MYD88 palmitoylation represents a promising therapeutic strategy for sepsis.