Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation
Introduction: Intracellular cAMP receptor exchange proteins directly activated by cAMP 1 (<i>EPAC1</i>) regulate obligate intracellular parasitic bacterium rickettsial adherence to and invasion into vascular endothelial cells (ECs). However, underlying precise mechanism(s) remain unclear...
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MDPI AG
2021-10-01
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author | Zhengchen Su Thomas R. Shelite Yuan Qiu Qing Chang Maki Wakamiya Jiani Bei Xi He Changcheng Zhou Yakun Liu Emmanuel Nyong Yuejin Liang Angelo Gaitas Tais B. Saito Bin Gong |
author_facet | Zhengchen Su Thomas R. Shelite Yuan Qiu Qing Chang Maki Wakamiya Jiani Bei Xi He Changcheng Zhou Yakun Liu Emmanuel Nyong Yuejin Liang Angelo Gaitas Tais B. Saito Bin Gong |
author_sort | Zhengchen Su |
collection | DOAJ |
description | Introduction: Intracellular cAMP receptor exchange proteins directly activated by cAMP 1 (<i>EPAC1</i>) regulate obligate intracellular parasitic bacterium rickettsial adherence to and invasion into vascular endothelial cells (ECs). However, underlying precise mechanism(s) remain unclear. The aim of the study is to dissect the functional role of the <i>EPAC1-ANXA2</i> signaling pathway during initial adhesion of rickettsiae to EC surfaces. Methods: In the present study, an established system that is anatomically based and quantifies bacterial adhesion to ECs in vivo was combined with novel fluidic force microscopy (FluidFM) to dissect the functional role of the <i>EPAC1-ANXA2</i> signaling pathway in rickettsiae–EC adhesion. Results: The deletion of the <i>EPAC1</i> gene impedes rickettsial binding to endothelium in vivo. Rickettsial OmpB shows a host <i>EPAC1</i>-dependent binding strength on the surface of a living brain microvascular EC (BMEC). Furthermore, ectopic expression of phosphodefective and phosphomimic mutants replacing tyrosine (Y) 23 of <i>ANXA2</i> in <i>ANXA2</i>-knock out BMECs results in different binding force to reOmpB in response to the activation of <i>EPAC1</i>. Conclusions: <i>EPAC1</i> modulates rickettsial adhesion, in association with Y23 phosphorylation of the binding receptor <i>ANXA2</i>. Underlying mechanism(s) should be further explored to delineate the accurate role of cAMP-<i>EPAC</i> system during rickettsial infection. |
first_indexed | 2024-03-10T06:16:54Z |
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language | English |
last_indexed | 2024-03-10T06:16:54Z |
publishDate | 2021-10-01 |
publisher | MDPI AG |
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series | Pathogens |
spelling | doaj.art-10fa23b1a045439db6392b9ddd130ac52023-11-22T19:34:01ZengMDPI AGPathogens2076-08172021-10-011010130710.3390/pathogens10101307Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 PhosphorylationZhengchen Su0Thomas R. Shelite1Yuan Qiu2Qing Chang3Maki Wakamiya4Jiani Bei5Xi He6Changcheng Zhou7Yakun Liu8Emmanuel Nyong9Yuejin Liang10Angelo Gaitas11Tais B. Saito12Bin Gong13Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADivision of Infectious Disease, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USAThe Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY 10029, USAThe Vector-Pathogen-Host Interaction Unit, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USAIntroduction: Intracellular cAMP receptor exchange proteins directly activated by cAMP 1 (<i>EPAC1</i>) regulate obligate intracellular parasitic bacterium rickettsial adherence to and invasion into vascular endothelial cells (ECs). However, underlying precise mechanism(s) remain unclear. The aim of the study is to dissect the functional role of the <i>EPAC1-ANXA2</i> signaling pathway during initial adhesion of rickettsiae to EC surfaces. Methods: In the present study, an established system that is anatomically based and quantifies bacterial adhesion to ECs in vivo was combined with novel fluidic force microscopy (FluidFM) to dissect the functional role of the <i>EPAC1-ANXA2</i> signaling pathway in rickettsiae–EC adhesion. Results: The deletion of the <i>EPAC1</i> gene impedes rickettsial binding to endothelium in vivo. Rickettsial OmpB shows a host <i>EPAC1</i>-dependent binding strength on the surface of a living brain microvascular EC (BMEC). Furthermore, ectopic expression of phosphodefective and phosphomimic mutants replacing tyrosine (Y) 23 of <i>ANXA2</i> in <i>ANXA2</i>-knock out BMECs results in different binding force to reOmpB in response to the activation of <i>EPAC1</i>. Conclusions: <i>EPAC1</i> modulates rickettsial adhesion, in association with Y23 phosphorylation of the binding receptor <i>ANXA2</i>. Underlying mechanism(s) should be further explored to delineate the accurate role of cAMP-<i>EPAC</i> system during rickettsial infection.https://www.mdpi.com/2076-0817/10/10/1307bacterial adhesionrickettsiaendothelial cell<i>EPAC1</i>annexin A2fluidic force microscopy |
spellingShingle | Zhengchen Su Thomas R. Shelite Yuan Qiu Qing Chang Maki Wakamiya Jiani Bei Xi He Changcheng Zhou Yakun Liu Emmanuel Nyong Yuejin Liang Angelo Gaitas Tais B. Saito Bin Gong Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation Pathogens bacterial adhesion rickettsia endothelial cell <i>EPAC1</i> annexin A2 fluidic force microscopy |
title | Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation |
title_full | Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation |
title_fullStr | Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation |
title_full_unstemmed | Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation |
title_short | Host EPAC1 Modulates Rickettsial Adhesion to Vascular Endothelial Cells via Regulation of ANXA2 Y23 Phosphorylation |
title_sort | host epac1 modulates rickettsial adhesion to vascular endothelial cells via regulation of anxa2 y23 phosphorylation |
topic | bacterial adhesion rickettsia endothelial cell <i>EPAC1</i> annexin A2 fluidic force microscopy |
url | https://www.mdpi.com/2076-0817/10/10/1307 |
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