Post-transcriptional Gene Regulation by EBV SM Protein

点击翻译按钮获取中文摘要

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.