Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation.
Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation.
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伪狂犬病病毒调控膜联蛋白A2胞外易位促进其增殖
DOI：
10.1128/jvi.01545-22
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发表时间：
2023-03-30
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
--
作者：
PRV属于甲型疱疹病毒，最近在中国重新出现，造成严重的经济损失。最近的研究还表明，PRV可能会对公共卫生构成潜在的挑战。伪狂犬病病毒(PRV)感染给养猪业造成了巨大的经济损失，给许多宿主带来了严重的健康后果。膜联蛋白A2(ANXA2)是一种膜相关蛋白，具有多种细胞内功能，与多种病毒感染相关。然而，ANXA2在甲型疱疹病毒复制中的作用仍未被探讨。在本研究中，我们确定了ANXA2和PRV US3之间的相互作用。ANXA2基因缺失显著抑制了PRV的增殖。PRV感染或US3过表达导致ANXA2胞外易位。此外，我们还证实了PRV或US3可以导致Tyr23ANXA2和Tyr419Src激酶的磷酸化，这与ANXA2细胞表面的转位有关。US3还能以不依赖于ANXA2的方式与Src结合，增强Src与ANXA2之间的相互作用。此外，针对ANXA2(A2ti-1)或Src(PP2)的抑制剂在体外能显著抑制PRV的繁殖，并能在体内保护小鼠免受PRV感染。总之，我们的发现加深了我们对ANXA2在甲型疱疹病毒致病中的分子机制的理解，并表明ANXA2是治疗甲型疱疹病毒引起的感染性疾病的潜在治疗靶点。重要PRV属于甲型疱疹病毒，最近在中国重新出现，造成严重的经济损失。最近的研究还表明，PRV可能会对公共卫生构成潜在的挑战。ANXA2是一种多功能的钙和脂结合蛋白，与免疫功能、多种人类疾病和病毒感染有关。在此，我们发现ANXA2对于PRV的高效增殖是必不可少的。PRV感染通过ANXA2和Src的磷酸化导致ANXA2的胞外转位。AnXA2和Src与PrV US3形成复合体。重要的是，针对ANXA2或Src的抑制剂在体外和体内都能预防PRV感染。因此，我们的研究揭示了一种新的策略，通过甲型疱疹病毒修饰ANXA2来促进其复制，并强调ANXA2是开发新型抗病毒药物的目标，在病毒治疗中具有广阔的前景。
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. ABSTRACT 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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影响因子：
5.4
作者：
Esteves AD;Koyuncu OO;Enquist LW
通讯作者：
Enquist LW
影响因子：
1.6
作者：
Calton, CM;Randall, JA;Banfield, BW
通讯作者：
Banfield, BW
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影响因子：
5
作者：
Li, Jiangnan;Guo, Dongwei;Weng, Changjiang
通讯作者：
Weng, Changjiang
影响因子：
1.5
作者：
Cramer, Sarah D.;Campbell, Gregory A.;Maes, Roger K.
通讯作者：
Maes, Roger K.
影响因子：
5.4
作者：
Jacob, Thary;Van den Broeke, Celine;Favoreel, Herman W.
通讯作者：
Favoreel, Herman W.