Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome

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.

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations

“…Interestingly, the top colocalisation (ZDHHC21) gene is implicated in lung vascular endothelial barrier integrity. 22 The p values of the top GWAS SNPs in ICGC located 500 kb up and downstream of genome-wide discovered genes varied from 1.71x10 -5 to 5.85x10 -4 , suggesting that the largest GWAS on COPD alone was underpowered to identify these genes at genome-wide significance. The findings support the utility of leveraging transcriptome data to uncover biologically relevant genes.…”

Endothelial Protrusions in Junctional Integrity and Barrier Function

“…In the brain, its leakage into the parenchyma is considered an indication of blood-brain barrier (BBB) disruption (Wang & Lai, 2014). EBD assays have proven reliable for determining gross microvascular leakage in many models and organs including the brain and lung (Yen et al , 2013; Beard et al , 2016). The classical methodology of this assay is that EBD is injected intravenously then tissue is collected, proteins are lysed and homogenized before checking the absorbance at 620 nm.…”

“…The balance of activities among members of the Rho family of small GTPases such as RhoA, Rac1, and Cdc42 have also been shown to be of importance for both disruption and stabilization of the endothelial barrier (Waschke et al , 2004a; Waschke et al , 2004b; Waschke et al , 2006; Baumer et al , 2008a; Schlegel et al , 2009; Schlegel & Waschke, 2009; Spindler et al , 2010; Breslin et al , 2015; Breslin et al , 2016; Zhang et al , 2016). In addition, there is increasing evidence that in addition to phosphorylation, other posttranslational modifications such as S-nitrosation of junctional proteins (Marin et al , 2012; Sánchez et al , 2013; Guequén et al , 2016), or specific palmitoylation of PKCβ by palmitoyl acyltransferase DHHC21 (Beard et al , 2016) can lead to elevated microvascular leakage.…”

S-Acylation of plant immune receptors mediates immune signaling in plasma membrane nanodomains

“…In human, a family of 24 DHHC-PATs was identified and shown to be involved in many physiological processes, as well as diseases spanning from neuropsychiatric disorders to cancers, cellular differentiation, melanomagenesis and so on (Chen et al, 2017b;De and Sadhukhan, 2018;Zhang and Hang, 2017). Most human DHHC-PATs are localized to endomembrane compartments such as Golgi, endosomes, endoplasmic reticulum, with only two proteins, DHHC20 and DHHC21, found at that the PM, which mediate epidermal growth factor receptor (EGFR) signaling in cancer and inflammatory responses (Beard et al, 2016;Runkle et al, 2016).…”