The guanine exchange factor SWAP70 mediates vGPCR-induced endothelial plasticity.

Julie Dwyer,Steven Georges,Lucas Treps,Eva M Galan-Moya,Nicolas Dupin,Héloïse M Leclair,Sandy Azzi,Agnès Carlotti,Nicolas Bidère,Catherine Alexia,Julie Gavard

doi:10.1186/s12964-015-0090-1

Abstract

BackgroundThe viral G protein-coupled receptor (vGPCR) is proposed to act as one of the predominant mediators of Kaposi’s sarcoma (KS), a human herpes virus 8 (HHV8)-elicited disease. The actions of vGPCR manifest pathogenesis, in part, through increased permeability of endothelial cells. Endothelial cell-cell junctions have indeed emerged as an instrumental target involved in the vasculature defects observed within the tumor microenvironment. The pathway leading to adherens junction destabilization has been shown to involve the activation of the small GTPase Rac, in the context of either latent infection or the sole expression of vGPCR. However, the precise molecular mechanisms governed by vGPCR in vascular leakage require further elucidation.FindingsGuanine exchange factors (GEFs) function as critical molecular switches that control the activation of small GTPases. We therefore screened the effects of 80 siRNAs targeting GEFs on vGPCR-driven endothelial permeability and identified switch-associated protein 70 (SWAP70) as necessary for its elevating effects. Pull-down experiments further showed that Rac activation by vGPCR was dependent on SWAP70. Examination of tissues and cells from HHV8-positive patients revealed that SWAP70 was ubiquitously expressed. Furthermore, SWAP70 was found to be crucial for vGPCR-driven endothelial tube formation and endothelial sprouting in vitro.ConclusionsSWAP70 appears to act as a molecular intermediate between vGPCR and endothelial activation. Because of the important role of vGPCR-mediated endothelial plasticity in KS pathogenesis, inhibition of SWAP70 function could be of interest for blocking vGPCR-driven activities in HHV8-defined diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-015-0090-1) contains supplementary material, which is available to authorized users.

Highlights

The viral G protein-coupled receptor is proposed to act as one of the predominant mediators of Kaposi’s sarcoma (KS), a human herpes virus 8 (HHV8)-elicited disease
Because of the important role of viral G protein-coupled receptor (vGPCR)-mediated endothelial plasticity in KS pathogenesis, inhibition of switch-associated protein 70 (SWAP70) function could be of interest for blocking vGPCR-driven activities in HHV8-defined diseases
Of the multiple genes encoded by the human herpes virus 8 (HHV8), the viral G protein-coupled receptor is one of the key instigators of Kaposi’s sarcoma (KS) pathogenesis [1]. vGPCR exhibits pleiotropic actions in the manifestation of diseases such as KS and primary effusion lymphoma (PEL), among which are paracrine transformation and endothelial defects [2,3,4,5,6,7]

Summary

Introduction

The viral G protein-coupled receptor (vGPCR) is proposed to act as one of the predominant mediators of Kaposi’s sarcoma (KS), a human herpes virus 8 (HHV8)-elicited disease. Using well-established methodologies, endothelial permeability was measured by the passage of FITC-conjugated 40 kDa dextran through a monolayer of human umbilical vein endothelial cells (HUVEC)-expressing vGPCR (Figure 1A; Additional file 1) [5,13]. Of the eighty GEFs screened, 29 were identified which, when silenced, decreased vGPCR-induced permeability by greater than 50% (Figure 1B; Additional file 2: Table S1).

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