4月17日，国际学术期刊Journal of Virology 在线发表了中国科学院上海巴斯德研究所蓝柯组的研究论文Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Interacts with Host KAP1 to Facilitate Establishment of Viral Latency（《卡波氏肉瘤相关疱疹病毒潜伏态核抗原与宿主KAP1分子相互作用促进病毒潜伏感染的建立》）。

　　卡波氏肉瘤病毒（KSHV）是一种致瘤性疱疹病毒，具有疱疹病毒的典型特征：存在潜伏感染和裂解性复制两种不同的生命周期。在宿主原发感染KSHV后，KSHV能很快地（一般在24-48小时内）在宿主体内建立潜伏感染并伴随宿主终生。在宿主体内，KSHV建立潜伏感染是其致病的必要条件，并在其生命周期中占据主导地位。因此，揭示KSHV在感染宿主细胞后迅速建立潜伏感染的机制将为探索相关疾病有效防治手段提供线索。

　　在KSHV感染早期阶段，裂解期基因会有一个短期的表达过程并随即沉默。前期研究发现KSHV编码的潜伏态核抗原（LANA）对调控病毒潜伏感染的建立和维持起关键作用，缺失LANA的KSHV会导致病毒基因组的丢失并促进裂解期基因的表达。此外，LANA蛋白能通过抑制病毒激活开关分子RTA启动子的活性下调其表达，但具体机制未完全阐明。

　　研究人员通过串联亲和层析技术，发现了与LANA相互作用的新的宿主转录抑制蛋白KAP1，KAP1可以通过招募组蛋白去乙酰化酶和甲基转移酶复合物改变表观遗传状态。通过免疫共沉淀、体外结合和免疫荧光实验，研究证实了LANA和KAP1的直接相互作用以及细胞核内的共定位，并测定出LANA与KAP1的N端、C端同时结合；通过染色质免疫共沉淀和荧光素酶报告基因实验，进一步证实了LANA可以将KAP1招募到KSHV RTA启动子区域并抑制RTA的表达。

    为了探究LANA是否会招募KAP1到KSHV基因组其它区域，研究人员通过染色质免疫共沉淀-深度测序技术(ChIP-seq)，证实了LANA和KAP1在KSHV基因组上有多个共结合位点。在KSHV从头感染实验中，LANA招募的KAP1被证明对KSHV感染的早期阶段裂解期基因表达的关闭起到重要作用。此项研究揭示了在KSHV感染早期阶段LANA对裂解期基因转录抑制的机制，为了解KSHV潜伏感染的建立过程提供了新线索。

　　此项研究在中科院马普计算生物学研究所Omics Core的技术支持和研究员蓝柯的指导下，由博士研究生孙锐和研究组其他成员共同完成，并获得了国家自然科学基金重点项目及国家“973”计划等项目的经费支持。

原文摘要：

Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Interacts with Host KAP1 to Facilitate Establishment of Viral Latency

Kaposi's sarcoma-associated herpesvirus (KSHV) typically displays two different phases in its life cycle, including the default latent phase as well as the lytic phase. There is a short period of lytic gene expression at the early stage of KSHV primary infection. The factors involved in the shutdown process of lytic gene expression are poorly identified. It has been shown that the latency-associated nuclear antigen (LANA) encoded by KSHV plays an important role in the establishment of viral latency. In screening, we identified a host protein, Krüppel-associated box domain associated protein-1 (KAP1) that bound to LANA. We validated the interaction between LANA and KAP1 in vivo and in vitro as well as their colocalization in the nucleus. We mapped out that LANA interacted with both the N- and C-terminal domains of KAP1. Based on the determined interface of LANA-KAP1 interaction, we proved that LANA recruited KAP1 to the RTA promoter region of the KSHV genome. We revealed that KAP1 was involved in transcriptional repression by LANA. We found that multiple co-occupation sites of LANA and KAP1 on the whole KSHV genome by ChIP-seq and demonstrated that LANA-recruited KAP1 played a critical role in the shutdown of lytic gene expression during the early stage of KSHV primary infection. Taken together, our data suggest that LANA interacts with KAP1 and represses lytic gene expression to facilitate the establishment of KSHV latency.

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