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Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome

Author

Listed:
  • Richard S. Beard

    (Morsani College of Medicine, University of South Florida)

  • Xiaoyuan Yang

    (Morsani College of Medicine, University of South Florida)

  • Jamie E. Meegan

    (Morsani College of Medicine, University of South Florida)

  • Jonathan W. Overstreet

    (Morsani College of Medicine, University of South Florida)

  • Clement G.Y. Yang

    (Morsani College of Medicine, University of South Florida)

  • John A. Elliott

    (Morsani College of Medicine, University of South Florida)

  • Jason J. Reynolds

    (Morsani College of Medicine, University of South Florida)

  • Byeong J. Cha

    (Morsani College of Medicine, University of South Florida)

  • Christopher D. Pivetti

    (School of Medicine, University of California at Davis)

  • David A. Mitchell

    (Morsani College of Medicine, University of South Florida)

  • Mack H. Wu

    (Morsani College of Medicine, University of South Florida
    James A. Haley Veterans' Hospital)

  • Robert J. Deschenes

    (Morsani College of Medicine, University of South Florida)

  • Sarah Y. Yuan

    (Morsani College of Medicine, University of South Florida
    Morsani College of Medicine, University of South Florida)

Abstract

Endothelial dysfunction is a hallmark of systemic inflammatory response underlying multiple organ failure. Here we report a novel function of DHHC-containing palmitoyl acyltransferases (PATs) in mediating endothelial inflammation. Pharmacological inhibition of PATs attenuates barrier leakage and leucocyte adhesion induced by endothelial junction hyperpermeability and ICAM-1 expression during inflammation. Among 11 DHHCs detected in vascular endothelium, DHHC21 is required for barrier response. Mice with DHHC21 function deficiency (Zdhhc21dep/dep) exhibit marked resistance to injury, characterized by reduced plasma leakage, decreased leucocyte adhesion and ameliorated lung pathology, culminating in improved survival. Endothelial cells from Zdhhc21dep/dep display blunted barrier dysfunction and leucocyte adhesion, whereas leucocytes from these mice did not show altered adhesiveness. Furthermore, inflammation enhances PLCβ1 palmitoylation and signalling activity, effects significantly reduced in Zdhhc21dep/dep and rescued by DHHC21 overexpression. Likewise, overexpression of wild-type, not mutant, PLCβ1 augments barrier dysfunction. Altogether, these data suggest the involvement of DHHC21-mediated PLCβ1 palmitoylation in endothelial inflammation.

Suggested Citation

  • Richard S. Beard & Xiaoyuan Yang & Jamie E. Meegan & Jonathan W. Overstreet & Clement G.Y. Yang & John A. Elliott & Jason J. Reynolds & Byeong J. Cha & Christopher D. Pivetti & David A. Mitchell & Mac, 2016. "Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome," Nature Communications, Nature, vol. 7(1), pages 1-19, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12823
    DOI: 10.1038/ncomms12823
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