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Protein palmitoylation regulates extracellular vesicle production and function in sepsis
Xiaoyuan Yang1, Ethan Zheng1, Victor Chatterjee1
1Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida, USA.
Journal of Extracellular Biology
|February 29, 2024
Summary
Palmitoylation regulates extracellular vesicle (EV) production and function during sepsis. Blocking DHHC21-mediated palmitoylation reduces sepsis-induced EVs, decreasing neutrophil activation and improving survival.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Extracellular vesicles (EVs) are key mediators of intercellular communication.
- Palmitoylation is a lipid modification affecting protein localization and function.
- The role of palmitoylation in EV biogenesis and sepsis pathophysiology is largely unknown.
Purpose of the Study:
- To investigate the role of palmitoylation, specifically DHHC21, in regulating EV formation and function during sepsis.
- To determine the impact of DHHC21 deficiency on EV composition and inflammatory potential.
- To assess the therapeutic potential of targeting palmitoylation in sepsis.
Main Methods:
- Utilized a mouse model of sepsis (CLP) with DHHC21 functional deficiency (Zdhhc21-/-).
- Quantified circulating EVs and analyzed their palmitoyl-proteomic profiles.
- Assessed EV-mediated effects on neutrophil adhesion, transmigration, and extracellular trap (NET) production.
- Evaluated neutrophil infiltration in lungs and animal survival rates.
Main Results:
- DHHC21 deficiency significantly reduced circulating EVs in septic mice.
- EVs from septic wild-type mice showed enrichment in complement pathway components, which was blunted in Zdhhc21-/- EVs.
- EVs from septic wild-type mice enhanced neutrophil functions, an effect attenuated by DHHC21 loss-of-function.
- Zdhhc21-/- mice exhibited reduced lung neutrophil infiltration and improved survival post-sepsis induction.
Conclusions:
- Palmitoylation, mediated by DHHC21, is a novel regulator of EV production and function in sepsis.
- Targeting DHHC21-dependent palmitoylation reduces the pro-inflammatory potential of sepsis-associated EVs.
- DHHC21 deficiency offers a protective effect in sepsis by modulating EV-mediated neutrophil responses.
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