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Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation

Pseudorabies virus (PRV) infection causes enormous economic losses to the pork industry and severe health consequences in many hosts. Annexin A2 (ANXA2) is a membrane-associated protein with various intracellular functions associated with many viral infections. However, the role of ANXA2 in alphaher...

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Autores principales: Weng, Maoyang, Guo, Zhenhua, Lu, Qingxia, Jin, Qianyue, Jiang, Yao, Wang, Fangyu, Guo, Junqing, Xing, Guangxu, Qiao, Songlin, Zhang, Gaiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062141/
https://www.ncbi.nlm.nih.gov/pubmed/36786600
http://dx.doi.org/10.1128/jvi.01545-22
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author Weng, Maoyang
Guo, Zhenhua
Lu, Qingxia
Jin, Qianyue
Jiang, Yao
Wang, Fangyu
Guo, Junqing
Xing, Guangxu
Qiao, Songlin
Zhang, Gaiping
author_facet Weng, Maoyang
Guo, Zhenhua
Lu, Qingxia
Jin, Qianyue
Jiang, Yao
Wang, Fangyu
Guo, Junqing
Xing, Guangxu
Qiao, Songlin
Zhang, Gaiping
author_sort Weng, Maoyang
collection PubMed
description Pseudorabies virus (PRV) infection causes enormous economic losses to the pork industry and severe health consequences in many hosts. Annexin A2 (ANXA2) is a membrane-associated protein with various intracellular functions associated with many viral infections. However, the role of ANXA2 in alphaherpesvirus replication is still not explored. In the present study, we identified the interaction between ANXA2 and PRV US3. The deficiency of ANXA2 significantly restricted PRV proliferation. PRV infection or US3 overexpression led to ANXA2 extracellular translocation. Furthermore, we confirmed that PRV or US3 could lead to the phosphorylation of the Tyr23 ANXA2 and Tyr419 Src kinase, which was associated with the ANXA2 cell surface transposition. US3 can also bind to Src in an ANXA2-independent manner and enhance the interaction between Src and ANXA2. Additionally, inhibitors targeting ANXA2 (A2ti-1) or Src (PP2) could remarkably inhibit PRV propagation in vitro and protect mice from PRV infection in vivo. Collectively, our findings broaden our understanding of the molecular mechanisms of ANXA2 in alphaherpesvirus pathogenicity and suggest that ANXA2 is a potential therapeutic target for treating alphaherpesvirus-induced infectious diseases. IMPORTANCE PRV belongs to the alphaherpesvirus and has recently re-emerged in China, causing severe economic losses. Recent studies also indicate that PRV may pose a potential public health challenge. ANXA2 is a multifunctional calcium- and lipid-binding protein implicated in immune function, multiple human diseases, and viral infection. Herein, we found that ANXA2 was essential to PRV efficient proliferation. PRV infection resulted in the extracellular translocation of ANXA2 through phosphorylation of ANXA2 and Src. ANXA2 and Src formed a complex with PRV US3. Importantly, inhibitors targeting ANXA2 or Src prevented PRV infection in vitro and in vivo. Therefore, our studies reveal a novel strategy by which alphaherpesvirus modifies ANXA2 to promote its replication and highlight ANXA2 as a target in developing novel promising antivirus agents in viral therapy.
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spelling pubmed-100621412023-03-31 Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation Weng, Maoyang Guo, Zhenhua Lu, Qingxia Jin, Qianyue Jiang, Yao Wang, Fangyu Guo, Junqing Xing, Guangxu Qiao, Songlin Zhang, Gaiping J Virol Virus-Cell Interactions Pseudorabies virus (PRV) infection causes enormous economic losses to the pork industry and severe health consequences in many hosts. Annexin A2 (ANXA2) is a membrane-associated protein with various intracellular functions associated with many viral infections. However, the role of ANXA2 in alphaherpesvirus replication is still not explored. In the present study, we identified the interaction between ANXA2 and PRV US3. The deficiency of ANXA2 significantly restricted PRV proliferation. PRV infection or US3 overexpression led to ANXA2 extracellular translocation. Furthermore, we confirmed that PRV or US3 could lead to the phosphorylation of the Tyr23 ANXA2 and Tyr419 Src kinase, which was associated with the ANXA2 cell surface transposition. US3 can also bind to Src in an ANXA2-independent manner and enhance the interaction between Src and ANXA2. Additionally, inhibitors targeting ANXA2 (A2ti-1) or Src (PP2) could remarkably inhibit PRV propagation in vitro and protect mice from PRV infection in vivo. Collectively, our findings broaden our understanding of the molecular mechanisms of ANXA2 in alphaherpesvirus pathogenicity and suggest that ANXA2 is a potential therapeutic target for treating alphaherpesvirus-induced infectious diseases. IMPORTANCE PRV belongs to the alphaherpesvirus and has recently re-emerged in China, causing severe economic losses. Recent studies also indicate that PRV may pose a potential public health challenge. ANXA2 is a multifunctional calcium- and lipid-binding protein implicated in immune function, multiple human diseases, and viral infection. Herein, we found that ANXA2 was essential to PRV efficient proliferation. PRV infection resulted in the extracellular translocation of ANXA2 through phosphorylation of ANXA2 and Src. ANXA2 and Src formed a complex with PRV US3. Importantly, inhibitors targeting ANXA2 or Src prevented PRV infection in vitro and in vivo. Therefore, our studies reveal a novel strategy by which alphaherpesvirus modifies ANXA2 to promote its replication and highlight ANXA2 as a target in developing novel promising antivirus agents in viral therapy. American Society for Microbiology 2023-02-14 /pmc/articles/PMC10062141/ /pubmed/36786600 http://dx.doi.org/10.1128/jvi.01545-22 Text en Copyright © 2023 Weng et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Virus-Cell Interactions
Weng, Maoyang
Guo, Zhenhua
Lu, Qingxia
Jin, Qianyue
Jiang, Yao
Wang, Fangyu
Guo, Junqing
Xing, Guangxu
Qiao, Songlin
Zhang, Gaiping
Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title_full Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title_fullStr Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title_full_unstemmed Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title_short Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation
title_sort pseudorabies virus regulates the extracellular translocation of annexin a2 to promote its proliferation
topic Virus-Cell Interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062141/
https://www.ncbi.nlm.nih.gov/pubmed/36786600
http://dx.doi.org/10.1128/jvi.01545-22
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