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The E301R protein of African swine fever virus functions as a sliding clamp involved in viral genome replication

文献类型： 外文期刊

作者： Li, Su;Ge, Hailiang;Li, Yanhua;Zhang, Kehui;Yu, Shaoxiong;Cao, Hongwei;Wang, Yanjin;Deng, Hao;Li, Jiaqi;Dai, Jingwen;Li, Lian-Feng;Luo, Yuzi;Sun, Yuan;Geng, Zhi;Dong, Yuhui;Zhang, Heng;Qiu, Hua-Ji

作者机构：

关键词： African swine fever virus;E301R protein;sliding clamp;DNA polymerase;genomic replication

期刊名称： MBIO

ISSN： 2150-7511

年卷期： 2023 年

页码：

收录情况： SCIE（2023版）

摘要： African swine fever virus (ASFV) is a complex nucleocytoplasmic, large DNA virus that infects both domestic pigs and wild boar, but little is known about the process of genomic replication. The E301R protein (pE301R) from ASFV was previously predicted as a proliferating cell nuclear antigen (PCNA)-like protein through clamping DNA polymerase to the DNA duplex, but its exact structure and functions remain uncharacterized. Here, the crystal structure of pE301R revealed that it is composed of structurally similar head and tail domains and shares significant structural similarities to the DNA polymerase processivity factors, including sliding clamp and eukaryotic PCNA. More specifically, we demonstrated that pE301R exhibited multiple oligomeric states (with dimers and tetramers dominant), and the tetramers are consistent with the ring-shaped homotetramers in a head-to-tail manner generated by crystal packing. We also showed that pE301R interacted with the ASFV genome and viral DNA polymerase O174L. Furthermore, knockdown of E301R by specific small interfering RNAs (siRNAs) significantly decreased the virus genomic replication. Interestingly, the downregulation of PCNA by siRNAs significantly decreased the cell viability, whereas the inhibitory effect was reversed by pE301R overexpression. Notably, we demonstrated that overexpression of PCNA partially restored ASFV replication upon transfection of siRNAs targeting E301R. More importantly, T2 amino alcohol, a PCNA-specific inhibitor, markedly inhibited ASFV replication at the stage of viral genome replication. Taken together, we revealed that pE301R functions as a sliding clamp in ASFV genomic replication and can be used as a potential antiviral target.

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