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Structure-function insights into the dual role of African swine fever virus pB318L: A typical geranylgeranyl-diphosphate synthase and a nuclear import protein

文献类型： 外文期刊

作者： Zhao, Hai-Fan;Wang, Ying;Liu, Xiao-Hong;Liu, Xian-Hui;Geng, Zhi;Gao, Zeng-Qiang;Huang, Li;Weng, Chang-Jiang;Dong, Yu-Hui;Zhang, Heng

作者机构：

关键词： African swine fever virus (ASFV);Prenyltransferase;Geranylgeranyl-diphosphate synthase;Crystal structure;Nuclear localization signal;Immune evasion

期刊名称： VIROLOGICA SINICA

ISSN： 1674-0769

年卷期： 2025 年 40 卷 2 期

页码：

收录情况： SCIE（2025版） ; ; CSCD（2025-2026年度） ; ; 科技核心（2024版）

摘要： African swine fever virus (ASFV) pB318L is an important protein for viral replication that acts as a membrane-bound trans-geranylgeranyl-diphosphate synthase (GGPPS) catalyzing the condensation of isopentenyl diphosphate (IPP) with allylic diphosphates. Recently we solved the crystal structure pB318L lacking N-terminal transmembrane region and performed a preliminary structural analysis. In this study, structure-based mutagenesis study and geranylgeranyl pyrophosphate (GGPP) production assay further revealed the key residues for the GGPPS activity. Structural comparison showed pB318L displays a strong similarity to typical GGPPSs instead of protein prenyltransferases. The phylogenetic analysis indicated pB318L may share a common ancestor with the GGPPSs from Brassicaceae plants rather than from its natural host. The subcellular localization analysis showed pB318L is localized in both nucleus and cytoplasm (including the endoplasmic reticulum membrane and mitochondria outer membrane). A unique N-terminal nuclear localization signal (NLS) following the transmembrane region was discovered in pB318L and the NLS was confirmed to be required for the nuclear import. We further revealed the NLS plays an essential role in the interaction with nuclear transporter karyopherin subunit alpha 1 (KPNA1). Their interaction may suppress signal transducers and activators of transcription 1 (STAT1) translocation and subsequently competitively inhibit nuclear import of IFNstimulated gene factor 3 (ISGF3) complex. Our biochemical, structural and cellular analyses provide novel insights to pB318L that acts as an essential GGPPS that promotes viral replication and as a nuclear import protein that may be involved in immune evasion of ASFV.

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