Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Contributes to Viral Latent Replication by Activating Phosphorylation of Survivin
Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Contributes to Viral Latent Replication by Activating Phosphorylation of Survivin
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DOI：
10.1128/jvi.03855-13
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发表时间：
2014-04-01
影响因子：
5.4
通讯作者：
Robertson, Erle S.
中科院分区：
文献类型：
--
作者：
Lu, Jie;Jha, Hem C.;Robertson, Erle S.
卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）是一种与卡波西肉瘤（Kaposi's sarcoma-associated herpesvirus，KS）、多中心Castleman病（multicentric Castleman's disease，MCD）和原发性渗出性淋巴瘤（primary effusion lymphoma，PEL）偶然相关的人类γ疱疹病毒。以前，我们发现由KSHV编码的拉娜上调凋亡抑制因子（IAP）家族成员生存素的表达。这导致KSHV感染的B细胞的细胞增殖速率增加。拉娜是将KSHV附加体拴系到宿主染色体上所必需的，并有效地将病毒基因组分离到分裂的肿瘤细胞中。在这里，我们表明，拉娜与极光激酶B（AK-B）相互作用，并诱导磷酸化的生存素残基T34。存活素特异性磷酸化残基T34增强p300的活性并抑制组蛋白脱乙酰基酶1（HDAC-1）的活性，然后导致病毒基因组上组蛋白H3乙酰化的增加。在KSHV感染的B细胞中，存活素特异性磷酸化T34残基上调组蛋白乙酰转移酶和脱乙酰酶的活性，从而导致病毒拷贝数增加。这导致潜伏感染的B淋巴瘤细胞中KSHV复制的增强。研究表明，拉娜也可以发挥作用，以调节病毒复制前的有丝分裂的潜伏感染的细胞，这表明，拉娜具有一个新的作用，在调节KSHV复制在感染的B细胞。重要性这项工作代表了一份报告的KSHV潜伏蛋白拉娜和它的相互作用与AK-B导致诱导磷酸化的癌蛋白生存素在残基T34。T34残基上的存活素特异性磷酸化上调组蛋白乙酰转移酶和脱乙酰酶的活性。这导致KSHV感染的B细胞中病毒拷贝数的增加。这些研究支持拉娜在KSHV感染的B细胞中通过翻译后修饰调节KSHV复制的作用。
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV-infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells.IMPORTANCEThis work represents a report of KSHV latent protein LANA and its interactions with AK-B leading to induction of phosphorylation of the oncoprotein survivin at residue T34. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases. This leads to an increase in viral copy number in KSHV-infected B cells. These studies support a role for LANA in regulating KSHV replication through posttranslation modification in KSHV-infected B cells.