中科院上海巴斯德研究所蓝柯研究组在在疱疹病毒调控宿主炎症反应研究中取得新进展，相关研究论文在线发表在6月22日国际病毒学知名学术期刊《病毒学期刊》（Journal of Virology）上。
上海巴斯德研究所的博士研究生李小凡、梁德光等是该论文的第一作者，蓝柯研究员为论文的通讯作者。该研究课题得到了国家973计划、国家自然科学基金、中国科学院“百人计划” 以及赛诺菲-安万特-中科院上海生命科学研究院优秀青年人才基金项目的资助。
卡波氏肉瘤相关疱疹病毒（Kaposi’s sarcoma associated herpesvirus, KSHV）是一种人类肿瘤病毒，是引起卡波氏肉瘤（Kaposi’s sarcoma, KS）、原发性渗出性淋巴瘤（Primary effusion lymphoma, PEL）以及多中心性 Castleman病（Multicentric Castleman disease, MCD）的病原体。KSHV 能够成功地在宿主体内建立终身潜伏感染。以往的研究表明，从KSHV原发感染到建立潜伏感染的过程中，KSHV编码的一系列功能蛋白通过抑制宿主细胞的固有免疫应答来逃避宿主的清除，但对已经建立潜伏感染的KSHV如何应对其它病原体感染触发的宿主急性炎症反应一直不清楚。
在新研究中，李小凡等发现KSHV潜伏感染或者过表达病毒潜伏基因LANA-1的血管内皮细胞对促炎症因子TNF-α的应答受到明显的抑制：TNF-α刺激后血管内皮细胞IL-8的mRNA水平和细胞培养液中IL-8的含量较对照细胞有明显的下调，并且细胞培养液对人中性粒细胞 (neutrophil)的趋化作用明显降低。报告基因研究表明，LANA-1能有效地阻断介导炎症反应的NF-κB信号通路。进一步的工作揭示，LANA-1能够利用宿主细胞的多泛素化修饰介导的蛋白降解途径，特异地降解细胞核内的NF-κB成员p65的蛋白水平，从而抑制NF-κB信号通路的激活。具体地，LANA-1与细胞核内的p65相互作用，并将其招募至细胞泛素连接酶elonginB/C-cullin5复合体中，增强p65的多泛素化修饰介导的降解。
该工作揭示了KSHV重要的潜伏期相关基因LANA-1是急性炎症反应的负调控因子，深化了人们对于KSHV和宿主固有免疫之间相互关系的认识。（生物谷Bioon.com）
生物谷推荐原味出处：
Journal of Virology doi:10.1128/JVI.00733-11
Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65
Xiaofan Li, Deguang Liang, Xianzhi Lin, Erle S. Robertson, and Ke Lan
Latency-associated nuclear antigen (LANA)-1 of Kaposi's sarcoma-associated herpesvirus (KSHV) is the major viral latent protein and functions as a multifaceted protein. Here, we report that LANA-1 attenuates endothelial response to tumor necrosis factor (TNF)-α stimulation and inhibits consequent neutrophil chemotaxis. Reporter assay showed that LANA-1 constantly repressed nuclear factor (NF)-B transactivity upon TNF-α stimulation. We also found that LANA-1 decreased nuclear p65 protein level through enhancement of poly-ubiquitylation-mediated p65 degradation, and an ElonginB/C-Cullin5-LANA-1-p65 complex assembled by LANA-1 was responsible for this enhanced p65 degradation. In telomerase-immortalized human umbilical vein endothelial cells, LANA-1 was demonstrated to repress interleukin-8 expression, which was involved in neutrophil recruitment to the inflammatory site. Through an in vitro transmigration assay, we determined a suppressive effect of LANA-1 on neutrophil chemotaxis. Our work suggests that KSHV LANA-1 is a negative modulator of acute inflammation, and shed light on a new mechanism by which latently infected KSHV evades the host innate immune response.
