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Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

Kaposi’s sarcoma–associated herpesvirus (KSHV) has been implicated in the pathogenesis of Kaposi’s sarcoma (KS) and other malignancies. The cellular origin of KS has been suggested to be either mesenchymal stem cells (MSCs) or endothelial cells. However, receptor(s) for KSHV to infect MSCs remains u...

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Autores principales: Lu, Zheng-Zhou, Sun, Cong, Zhang, Xiaolin, Peng, Yingying, Wang, Yan, Zeng, Yan, Zhu, Nannan, Yuan, Yan, Zeng, Mu-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10208568/
https://www.ncbi.nlm.nih.gov/pubmed/37224259
http://dx.doi.org/10.1126/sciadv.adg1778
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author Lu, Zheng-Zhou
Sun, Cong
Zhang, Xiaolin
Peng, Yingying
Wang, Yan
Zeng, Yan
Zhu, Nannan
Yuan, Yan
Zeng, Mu-Sheng
author_facet Lu, Zheng-Zhou
Sun, Cong
Zhang, Xiaolin
Peng, Yingying
Wang, Yan
Zeng, Yan
Zhu, Nannan
Yuan, Yan
Zeng, Mu-Sheng
author_sort Lu, Zheng-Zhou
collection PubMed
description Kaposi’s sarcoma–associated herpesvirus (KSHV) has been implicated in the pathogenesis of Kaposi’s sarcoma (KS) and other malignancies. The cellular origin of KS has been suggested to be either mesenchymal stem cells (MSCs) or endothelial cells. However, receptor(s) for KSHV to infect MSCs remains unknown. By combining bioinformatics analysis and shRNA screening, we identify neuropilin 1 (NRP1) as an entry receptor for KSHV infection of MSCs. Functionally, NRP1 knockout and overexpression in MSCs significantly reduce and promote, respectively, KSHV infection. Mechanistically, NRP1 facilitated the binding and internalization of KSHV by interacting with KSHV glycoprotein B (gB), which was blocked by soluble NRP1 protein. Furthermore, NRP1 interacts with TGF-β receptor type 2 (TGFBR2) through their respective cytoplasmic domains and thus activates the TGFBR1/2 complex, which facilitates the macropinocytosis-mediated KSHV internalization via the small GTPases Cdc42 and Rac1. Together, these findings implicate that KSHV has evolved a strategy to invade MSCs by harnessing NRP1 and TGF-beta receptors to stimulate macropinocytosis.
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spelling pubmed-102085682023-05-25 Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis Lu, Zheng-Zhou Sun, Cong Zhang, Xiaolin Peng, Yingying Wang, Yan Zeng, Yan Zhu, Nannan Yuan, Yan Zeng, Mu-Sheng Sci Adv Biomedicine and Life Sciences Kaposi’s sarcoma–associated herpesvirus (KSHV) has been implicated in the pathogenesis of Kaposi’s sarcoma (KS) and other malignancies. The cellular origin of KS has been suggested to be either mesenchymal stem cells (MSCs) or endothelial cells. However, receptor(s) for KSHV to infect MSCs remains unknown. By combining bioinformatics analysis and shRNA screening, we identify neuropilin 1 (NRP1) as an entry receptor for KSHV infection of MSCs. Functionally, NRP1 knockout and overexpression in MSCs significantly reduce and promote, respectively, KSHV infection. Mechanistically, NRP1 facilitated the binding and internalization of KSHV by interacting with KSHV glycoprotein B (gB), which was blocked by soluble NRP1 protein. Furthermore, NRP1 interacts with TGF-β receptor type 2 (TGFBR2) through their respective cytoplasmic domains and thus activates the TGFBR1/2 complex, which facilitates the macropinocytosis-mediated KSHV internalization via the small GTPases Cdc42 and Rac1. Together, these findings implicate that KSHV has evolved a strategy to invade MSCs by harnessing NRP1 and TGF-beta receptors to stimulate macropinocytosis. American Association for the Advancement of Science 2023-05-24 /pmc/articles/PMC10208568/ /pubmed/37224259 http://dx.doi.org/10.1126/sciadv.adg1778 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Lu, Zheng-Zhou
Sun, Cong
Zhang, Xiaolin
Peng, Yingying
Wang, Yan
Zeng, Yan
Zhu, Nannan
Yuan, Yan
Zeng, Mu-Sheng
Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title_full Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title_fullStr Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title_full_unstemmed Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title_short Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis
title_sort neuropilin 1 is an entry receptor for kshv infection of mesenchymal stem cell through tgfbr1/2-mediated macropinocytosis
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10208568/
https://www.ncbi.nlm.nih.gov/pubmed/37224259
http://dx.doi.org/10.1126/sciadv.adg1778
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