近日，中山大学医学院徐培教授团队在Journal of Virology发表研究论文PML Body Component Sp100A Restricts Wild-Type Herpes Simplex Virus 1 Infection。发现Sp100A能有效抑制野生型 HSV-1的胞内复制和细胞间传播。 该研究团队之前曾研究发现细胞核内功能小体PML小体通过其成分蛋白Sp100A感应细胞质信号变化并参与/介导天然免疫的全新机制（详见之前报道 【前沿&进展】重磅！中山大学医学院徐培研究组揭示PML小体感应干扰素通路的新机制 。

人类单纯疱疹病毒I型（HSV-1）在人群中感染率极高，并且具有终身潜伏感染的特点。当病毒在免疫力低下人群中新发或复发时，容易发生系统性病毒扩散，侵染宿主中枢神经系统，甚至诱发脑膜炎等严重疾病。

Sp100是核内重要抗病毒结构和功能复合体PML小体的重要固有成分，包含四种亚型。前期研究表明，HSV-1感染引起细胞核内SUMO修饰的Sp100的迅速降解，但部分Sp100 亚型 A (Sp100A) Sp100A亚型蛋白不受病毒靶向。而这些残留的Sp100的蛋白在病毒复制过程中的作用并不明确。

本研究中，我们依次分析了各个 Sp100 亚型对 HSV-1 感染的作用，发现Sp100A能有效抑制野生型 HSV-1的胞内复制和细胞间传播。在HSV-1裂解性复制过程中，细胞核内的Sp100蛋白被病毒高效降解，但宿主细胞胞质中的Sp100A蛋白则通过外泌体的形式向被感染细胞外运送。胞外囊泡结构中的Sp100A蛋白能被未感染细胞有效接收，并抑制HSV-1病毒对这些细胞的侵染。

该项目主要工作由马懿磊博士，李京京硕士和董洪昌博士共同完成。徐培教授为该文通讯作者。该研究得到了国家自然基金和深圳市科技创新计划基金的支持。

Abstract：Sp100 (Speckled protein 100 kDa) is a constituent component of nuclear structure PML (promyelocytic leukemia) bodies, playing important roles in mediating intrinsic and innate immunity. The Sp100 gene encodes four isoforms with distinct roles in tranional regulation of both cellular and viral genes. Since Sp100 is a primary intranuclear target of infected-cell protein no. 0 (ICP0), an immediate early E3 ligase encoded by herpes simplex virus (HSV-1), prior investigations attempting to analyze the functions of individual Sp100 variants during HSV-1 infection mostly avoided using a wild-type virus. Therefore, the role of Sp100 under natural infection of HSV-1 remains to be clarified. Herein, we reappraised the antiviral capacity of four Sp100 isoforms during infection of a non-mutated HSV-1, examined the molecular behavior of Sp100 protein in detail and revealed the following intriguing observations: I) Sp100 isoform A (Sp100A) inhibited wild-type HSV-1 propagation in HEp-2, Sp100-/- and PML-/- cells. II) Endogenous Sp100 is in both the nucleus and the cytoplasm. During HSV-1 infection, nuclear Sp100 level decreased drastically upon detection of ICP0 in the same subcellular compartment, but cytosolic Sp100 remained stable. III) Transfected Sp100A shared similar subcellular localizations as endogenous Sp100 and matched the protein size of the endogenous cytosolic Sp100. IV) HSV-1 infection induced increased secretion of endogenous Sp100 and ectopically expressed Sp100A, which copurified with extracellular vesicles (EVs) but not infectious virions. V) Sp100A level in the secreting cells positively correlated with its level in EVs, and EV-associated Sp100A restricted HSV-1 in the recipient cells.

Importance：Previous studies show that the PML body component Sp100 protein is immediately targeted by ICP0 of HSV-1 in the nucleus during productive infection. Therefore, extensive studies investigating the interplay of Sp100 isoforms with HSV-1 were conducted using a mutant virus lacking ICP0 or in the absence of infection. The role of Sp100 variants during natural HSV-1 infection remains blurry. Here, we report that Sp100A potently and independently inhibited wild-type HSV-1 and that during HSV-1 infection, cytosolic Sp100 remained stable and was increasingly secreted into the extracellular space, in association with EVs. Furthermore, the Sp100A level in secreting cells positively correlated with its level in EVs and the anti-HSV-1 potency of these EVs in recipient cells. In summary, this study implies an active antiviral role of Sp100A during wild-type HSV-1 infection and reveals a novel mechanism of Sp100A to restrict HSV-1 through extracellular communications.