Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome

被引：50

作者：

Beard, Richard S., Jr. ^{[1
]}

Yang, Xiaoyuan ^{[1
]}

Meegan, Jamie E. ^{[1
]}

Overstreet, Jonathan W. ^{[1
]}

Yang, Clement G. Y. ^{[2
]}

Elliott, John A. ^{[1
]}

Reynolds, Jason J. ^{[1
]}

Cha, Byeong J. ^{[1
]}

Pivetti, Christopher D. ^{[3
]}

Mitchell, David A. ^{[4
]}

Wu, Mack H. ^{[2
,5
]}

Deschenes, Robert J. ^{[4
]}

Yuan, Sarah Y. ^{[1
,2
]}

机构：

[1] Univ S Florida, Morsani Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA

[2] Univ S Florida, Morsani Coll Med, Dept Surg, Tampa, FL 33612 USA

[3] Univ Calif Davis, Sch Med, Dept Surg, Sacramento, CA 95817 USA

[4] Univ S Florida, Morsani Coll Med, Dept Mol Med, Tampa, FL 33612 USA

[5] James A Haley Vet Hosp, Tampa, FL 33612 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家卫生研究院;

关键词：

ACUTE LUNG INJURY; MICROVASCULAR PERMEABILITY; PROTEIN PALMITOYLATION; IN-VITRO; BARRIER DYSFUNCTION; ACYL TRANSFERASES; GENE-EXPRESSION; SEVERE SEPSIS; BETA-CATENIN; CELLS;

D O I：

10.1038/ncomms12823

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (Zdhhc21(dep/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 Zdhhc21(dep/dep) display blunted barrier dysfunction and leucocyte adhesion, whereas leucocytes from these mice did not show altered adhesiveness. Furthermore, inflammation enhances PLC beta 1 palmitoylation and signalling activity, effects significantly reduced in Zdhhc21(dep/dep) and rescued by DHHC21 overexpression. Likewise, overexpression of wild-type, not mutant, PLC beta 1 augments barrier dysfunction. Altogether, these data suggest the involvement of DHHC21-mediated PLC beta 1 palmitoylation in endothelial inflammation.

引用

页数：19

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