Kaposi's Sarcoma-Associated Herpesvirus ORF21 Enhances the Phosphorylation of MEK and the Infectivity of Progeny Virus.
Kaposi's Sarcoma-Associated Herpesvirus ORF21 Enhances the Phosphorylation of MEK and the Infectivity of Progeny Virus.
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DOI：
10.3390/ijms24021238
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发表时间：
2023-01-08
影响因子：
5.6
通讯作者：
Fujimuro, Masahiro
中科院分区：
文献类型：
--
作者：
Yamaguchi, Tatsuo;Watanabe, Tadashi;Iwaisako, Yuki;Fujimuro, Masahiro
关键词：
卡波西肉瘤相关疱疹病毒(KSHV)，也被称为人类疱疹病毒-8，是卡波西肉瘤、Castleman病和原发渗出性淋巴瘤的病原体。虽然单纯疱疹病毒1/2的病毒胸苷激酶(VTK)的功能已被人们所熟知，但KSHV ORF21(vTK的同源基因)的功能却鲜为人知。在这里，我们通过产生两个ORF21突变的KSHV BAC克隆来研究ORF21在裂解复制和感染中的作用：ORF21-激酶活性缺陷的KSHV(21kD)和终止密码子诱导的ORF21-缺失的KSHV(21del)。结果表明，两个ORF21突变均不影响病毒基因组复制、裂解基因转录或病毒基因组包裹颗粒的产生。ORF21的分子依赖功能，而不是ORF21的激酶功能，参与了子代病毒的感染性。ORF21在裂解复制诱导后36h开始表达，内源性表达定位于整个细胞质。此外，ORF21还上调了MEK的磷酸化和锚定非依赖性细胞生长。U0126抑制受体靶细胞中的MEK信号，抑制了子代病毒感染细胞的数量。这些提示ORF21作为被膜蛋白在子代病毒中传播，通过在受体细胞中上调MEK来增强新的感染。我们的研究结果表明，ORF21通过对细胞功能的调控在KSHV感染过程中发挥关键作用。
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causative agent of Kaposi’s sarcoma, Castleman’s disease, and primary effusion lymphoma. Although the functions of the viral thymidine kinases (vTK) of herpes simplex virus-1/2 are well understood, that of KSHV ORF21 (an ortholog of vTK) is largely unknown. Here, we investigated the role of ORF21 in lytic replication and infection by generating two ORF21-mutated KSHV BAC clones: ORF21-kinase activity deficient KSHV (21KD) and stop codon-induced ORF21-deleted KSHV (21del). The results showed that both ORF21 mutations did not affect viral genome replication, lytic gene transcription, or the production of viral genome-encapsidated particles. The ORF21 molecule-dependent function, other than the kinase function of ORF21, was involved in the infectivity of the progeny virus. ORF21 was expressed 36 h after the induction of lytic replication, and endogenously expressed ORF21 was localized in the whole cytoplasm. Moreover, ORF21 upregulated the MEK phosphorylation and anchorage-independent cell growth. The inhibition of MEK signaling by U0126 in recipient target cells suppressed the number of progeny virus-infected cells. These suggest that ORF21 transmitted as a tegument protein in the progeny virus enhances the new infection through MEK up-regulation in the recipient cell. Our findings indicate that ORF21 plays key roles in the infection of KSHV through the manipulation of the cellular function.
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