An Epstein-Barr virus immediate-early gene product trans-activates gene expression from the human immunodeficiency virus long terminal repeat.

Patterson

et al. 2000

Homologs of the Epstein-Barr virus (EBV) SM protein exist in several human and nonhuman herpesviruses.Structure and function differ significantly among these proteins. We have cloned and characterized the human herpesvirus 8 (HHV8) gene, KS-SM, which is homologous to the EBV SM and herpes simplex virus ICP27 genes, from an HHV8-infected primary effusion lymphoma. KS-SM is shown to be a posttranscriptional activator of gene expression in cotransfection studies. KS-SM activated gene expression in a gene-specific, promoter-independent manner. In particular, KS-SM enhanced the expression of KDR/flk-1, a receptor for vascular endothelial growth factor (VEGF), in cotransfection studies. Since expression of KDR/flk-1 is increased in Kaposi's sarcoma and HHV8-infected cell cultures and VEGF enhances the proliferation of HHV8-infected cells, KS-SM may play a pathogenic role in Kaposi's sarcoma.

Section: Expression and Localization Of Ks-sm In Hhv8-infected And Ksmentioning

confidence: 65%

The Human Herpesvirus 8 Homolog of Epstein-Barr Virus SM Protein (KS-SM) Is a Posttranscriptional Activator of Gene Expression

Gupta

Patterson

et al. 2000

“…During lytic EBV replication, SM is expressed prior to other early genes but after the immediateearly genes BRLF1 and BZLF1. SM enhances the expression of several EBV genes and heterologous genes in cotransfection assays (30,31,39,52,55). Its ability to activate expression of cotransfected genes in a promoter-independent fashion has led to it being described as a promiscuous transactivator.…”

Section: Epstein-barr Virus (Ebv) a Human Gammaherpesvirus Is The Amentioning

confidence: 99%

The Epstein-Barr Virus SM Protein Induces STAT1 and Interferon-Stimulated Gene Expression

Navarro

Sample

et al. 2003

Viruses utilize numerous mechanisms to counteract the host's immune response. Interferon production is a major component of the host antiviral response. Many viruses, therefore, produce proteins or RNA molecules that inhibit interferon-induced signal transduction pathways and their associated antiviral effects. Surprisingly, some viruses directly induce expression of interferon-induced genes. SM, an early lytic Epstein-Barr virus (EBV) nuclear protein, was found to specifically increase the expression of several genes (interferonstimulated genes) that are known to be strongly induced by alpha/beta interferons. SM does not directly stimulate alpha/beta interferon secretion but instead induces STAT1, an intermediate step in the interferon signaling pathway. SM is a posttranscriptional activator of gene expression and increases STAT1 mRNA accumulation, particularly that of the functionally distinct STAT1␤ splice variant. SM expression in B lymphocytes is associated with decreased cell proliferation but does not decrease cell viability or induce cell cycle arrest. These results indicate that EBV can specifically induce cellular genes that are normally physiological targets of interferon by inducing components of cytokine signaling pathways. Our findings therefore suggest that some aspects of the interferon response may be positively modulated by infecting viruses. Epstein-Barr virus (EBV), a human gammaherpesvirus, is the agent of infectious mononucleosis and is associated withBurkitt lymphoma, nasopharyngeal carcinoma, and lymphomas in immunosuppressed hosts (for a review, see reference 32). Infection by human herpesviruses of all classes specifically modulates cellular-gene expression. Because herpesviruses establish lifelong infections in the face of a competent immune system, many of the cellular genes affected are components of the innate or adaptive immune response. For example, an EBV immediate-early gene product inhibits gamma interferon (IFN-␥) signaling and down-regulates expression of the IFN-␥ receptor (42).The EBV SM protein is a posttranscriptional gene regulatory protein expressed early during lytic replication (9,12,14,53,66). Homologues of SM are found in herpes simplex virus (HSV), human cytomegalovirus (CMV), varicella-zoster virus, and Kaposi's sarcoma-associated virus (human herpesvirus 8) and act as transcriptional and posttranscriptional regulators (2,10,17,26,29,33,40). During lytic EBV replication, SM is expressed prior to other early genes but after the immediateearly genes BRLF1 and BZLF1. SM enhances the expression of several EBV genes and heterologous genes in cotransfection assays (30,31,39,52,55). Its ability to activate expression of cotransfected genes in a promoter-independent fashion has led to it being described as a promiscuous transactivator. Further studies demonstrated that several genes containing introns were inhibited by SM, whereas intronless genes were activated by SM (52). The majority of cellular genes and latent EBV genes are spliced, whereas most lytic EBV genes are n...

“…SM enhances expression of several EBV genes and heterologous genes and is essential for virion production (13,20,21,23,31,36). SM protein binds mRNA in vitro and in vivo, shuttles from nucleus to cytoplasm, interacts with components of nuclear export pathways, and enhances the cytoplasmic accumulation of target gene RNA transcripts (3,4,10,29,36).…”

mentioning

confidence: 99%

Functional Analysis of Epstein-Barr Virus SM Protein: Identification of Amino Acids Essential for Structure, Transactivation, Splicing Inhibition, and Virion Production

Sun

Howard

et al. 2004

The Epstein-Barr virus (EBV) SM protein is a posttranscriptional regulator of cellular and viral gene expression that binds and stabilizes target mRNAs and shuttles from nucleus to cytoplasm. SM enhances expression of several EBV genes required for lytic replication and is essential for virion production. SM increases accumulation of specific mRNAs but also inhibits expression of several intron-containing transcripts. The mechanism by which SM inhibits gene expression is poorly understood. The experiments described here had several aims: to determine whether specific domains of SM were responsible for activation or inhibition function; whether these functions could be separated; and whether one or more of these functions were essential for virion production. A mutational analysis of SM was performed, focusing on amino acids in SM that are evolutionarily conserved among SM homologs in other herpesviruses. Mutation of the carboxyterminal region of SM revealed a region that is likely to be structurally important for SM protein conformation. In addition, several amino acids were identified that are critical for activation and inhibition function. A specific mutation of a highly conserved cysteine residue revealed that it was essential for gene inhibition but not for transactivation, indicating that these two functions operate through independent mechanisms. Furthermore, the ability of wild-type SM and the inability of the mutant to inhibit gene expression were shown to correlate with the ability to inhibit splicing of a human target gene and thereby prevent accumulation of its processed mRNA. Surprisingly, some mutations which preserved both activation and inhibition functions in vitro nevertheless abolished virion production, suggesting that other SM functions or protein-protein interactions are also required for lytic replication.