Post-transcriptional Gene Regulation by EBV SM Protein

描述(申请人提供)：Epstein-Barr病毒(EBV)是一种人类嗜淋巴疱疹病毒，与上皮性和淋巴增生性恶性肿瘤有关，包括Burkitt淋巴瘤、鼻咽癌和艾滋病相关淋巴瘤。免疫抑制的宿主具有更高水平的可检测到的裂解EBV复制和更大的病毒载量。因此，裂解复制基因的作用机制对于理解EBV感染的动力学很重要。一些EBV裂解基因，如EBV SM，本研究的主题，没有人类同源基因，因此也是有吸引力的治疗靶点。此外，EBV裂解蛋白与宿主基因有广泛的相互作用，既调节它们的表达，又调节它们的功能。了解这些相互作用可能有助于深入了解病毒复制和持久性的要求，以及细胞生长和转录后基因调控的基本方面。 EBV SM是EBV裂解复制早期表达的必需基因，对EBV和细胞基因表达具有转录后激活和抑制作用。SM在物理上与执行RNA处理和输出功能的细胞蛋白质相互作用。丹参稳定mRNA，促进特定EBV靶基因的mRNA输出，抑制许多剪接基因的表达，但也增加少量剪接细胞基因的表达。SM诱导作用最强的细胞基因是干扰素刺激基因(ISGs)家族的成员。 这个建议有四个主要目标：第一个目标是确定SM诱导的四个细胞质ISGs的功能，它们可能在宿主对病毒感染的反应中发挥重要作用。第二个是确定SM如何以基因特异性的方式增加mRNA水平，并描述其对EBV裂解基因表达的影响。第三个是确定SM与哪些细胞RNA加工蛋白相互作用以抑制剪接和改变剪接位点的选择。最后是确定一种名为Sp110b的PML身体蛋白的作用机制和细胞功能，SM诱导、结合和协同作用以激活基因表达。

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human lymphotropic herpesvirus causally associated with epithelial and lymphoproliferative malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma and AIDS-associated lymphoma. Immunosuppressed hosts have greater levels of detectable lytic EBV replication and greater viral loads. The mechanism of action of lytic replication genes is therefore important in understanding the dynamics of EBV infection. Some EBV lytic genes such as EBV SM, the subject of this study, have no human homologues and are therefore also attractive therapeutic targets. Moreover, EBV lytic proteins have extensive interactions with host genes, both regulating their expression and modulating their function. Understanding these interactions is likely to yield insights into the requirements for virus replication and persistence as well as fundamental aspects of cell growth and post-transcriptional gene regulation. EBV SM is an essential gene expressed early in EBV lytic replication that has both activating and inhibitory post-transcriptional effects on EBV and cell gene expression. SM physically interacts with cell proteins that carry out RNA processing and export functions. SM stabilizes mRNA and facilitates export of mRNA from specific EBV target genes and inhibits expression of many spliced genes, but also increases expression of a small number of spliced cellular genes. The cellular genes most highly induced by SM are members of a family of interferon-stimulated genes (ISGs). This proposal has four main objectives: The first is to determine the function of four cytoplasmic ISGs induced by SM which are likely to be important in the host response to viral infection. The second is to determine how SM increases mRNA levels in a gene-specific manner, and delineate its effects on EBV lytic gene expression. The third is to determine which cellular RNA processing proteins SM interacts with to inhibit splicing and alter splice-site selection. The last is to determine the mechanism of action and cellular function of a PML body protein known as Sp110b, which SM induces, binds to, and synergizes with to activate gene expression.