Targeting Ser78 phosphorylation of Hsp27 achieves potent antiviral effects against enterovirus A71 infection

作者全名：Wu, Mandi; Wan, Qianya; Dan, Xuelian; Wang, Yiran; Chen, Peiran; Chen, Cien; Li, Yichen; Yao, Xi; He, Ming-Liang

作者地址：[Wu, Mandi; Wan, Qianya; Dan, Xuelian; Wang, Yiran; Chen, Peiran; Chen, Cien; Li, Yichen; Yao, Xi; He, Ming-Liang] City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China; [Dan, Xuelian] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Minist Educ,Key Lab Mol Biol Infec, Chongqing, Peoples R China; [He, Ming-Liang] CityU Shenzhen Res Inst, Shenzhen, Peoples R China

通信作者：He, ML (通讯作者)，City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China.; He, ML (通讯作者)，CityU Shenzhen Res Inst, Shenzhen, Peoples R China.

来源：EMERGING MICROBES & INFECTIONS

ESI学科分类：MICROBIOLOGY

WOS号：WOS:001258220600001

JCR分区：Q1

影响因子：8.4

年份：2024

卷号：13

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Hsp27; enterovirus A71; antiviral; phosphorylation; hnRNP A1 translocation

摘要：A positive-sense (+) single-stranded RNA (ssRNA) virus (e.g. enterovirus A71, EV-A71) depends on viral polypeptide translation for initiation of virus replication after entry. We reported that EV-A71 hijacks Hsp27 to induce hnRNP A1 cytosol redistribution to initiate viral protein translation, but the underlying mechanism is still elusive. Here, we show that phosphorylation-deficient Hsp27-3A (Hsp27(S15/78/82A)) and Hsp27(S78A) fail to translocate into the nucleus and induce hnRNP A1 cytosol redistribution, while Hsp27(S15A) and Hsp27(S82A) display similar effects to the wild type Hsp27. Furthermore, we demonstrate that the viral 2A protease (2A(pro)) activity is a key factor in regulating Hsp27/hnRNP A1 relocalization. Hsp27(S78A) dramatically decreases the IRES activity and viral replication, which are partially reduced by Hsp27(S82A). However, Hsp27(S15A) displays the same activity as the wild-type Hsp27. Peptide S78 potently suppresses EV-A71 protein translation and reproduction through blockage of EV-A71-induced Hsp27 phosphorylation and Hsp27/hnRNP A1 relocalization. A point mutation (S78A) on S78 impairs its inhibitory functions on Hsp27/hnRNP A1 relocalization and viral replication. Taken together, we demonstrate the importance of Ser78 phosphorylation of Hsp27 regulated by virus infection in nuclear translocation, hnRNP A1 cytosol relocation, and viral replication, suggesting a new path (such as peptide S78) for target-based antiviral strategy. [GRAPHICS] .

基金机构：RGC General Research Fund of Hong Kong Special Administrative Region [11104020]; City University of Hong Kong [SRG-Fd 7005741, ARG 9667202, MFPRC 9680149]

基金资助正文：The work was partially supported by grants from RGC General Research Fund of Hong Kong Special Administrative Region [11104020] and Strategic funds from City University of Hong Kong (SRG-Fd 7005741, ARG 9667202 and MFPRC 9680149) to M. He.