A common mechanism links Epstein‐Barr virus infections and autoimmune diseases

Epstein‐Barr virus (EBV) infection is associated with a variety of the autoimmune diseases. There is apparently no unified model for the role of EBV in autoimmune diseases. In this article, the development of autoimmune diseases is proposed as a simple two‐step process: specific autoimmune initiators may cause irreversible changes to genetic materials that increase autoimmune risks, and autoimmune promoters promote autoimmune disease formation once cells are susceptible to autoimmunity. EBV has several types of latencies including type III latency with higher proliferation potential. EBV could serve as autoimmune initiators for some autoimmune diseases. At the same time, EBV may play a promotional role in majority of the autoimmune diseases by repeated replenishment of EBV type III latency cells and inflammatory cytokine productions in persistent stage. The type III latency cells have enhanced capacity as antigen‐presenting cells that would facilitate the development of both B and T cell‐mediated autoimmunity. The repeated cytokine productions are achieved by the repeated infection of naive B‐lymphocytes and proliferation of type III latency cells that produce inflammatory cytokines. Presentation of viral or self‐antigens by EBV type III latency B lymphocytes may promote autoreactive B cell and T cell proliferation, which can be amplified by type III latency cells‐mediated cytokines productions. Different autoimmune diseases may require different kinds of pathogenic immune cells and/or specific cytokines. Frequency of the replenishment of EBV type III latency cells may determine the specific effect of the promoter functions. A specific initiator plus EBV‐mediated common promoter function may lead to development of

Dual Functions of Interferon Regulatory Factors 7C in Epstein-Barr Virus–Mediated Transformation of Human B Lymphocytes

Epstein-Barr virus (EBV) infection is associated with several human malignancies. Interferon (IFN) regulatory factor 7 (IRF-7) has several splicing variants, and at least the major splicing variant (IRF-7A) has oncogenic potential and is associated with EBV transformation processes. IRF-7C is an alternative splicing variant with only the DNA-binding domain of IRF-7. Whether IRF-7C is present under physiological conditions and its functions in viral transformation are unknown. In this report, we prove the existence of IRF-7C protein and RNA in certain cells under physiological conditions, and find that high levels of IRF-7C are associated with EBV transformation of human primary B cells in vitro as well as EBV type III latency. EBV latent membrane protein 1 (LMP-1) stimulates IRF-7C expression in B lymphocytes. IRF-7C has oncogenic potential in rodent cells and partially restores the growth properties of EBV-transformed cells under a growth-inhibition condition. A tumor array experiment has identified six primary tumor specimens with high levels of IRF-7C protein—all of them are lymphomas. Furthermore, we show that the expression of IRF-7C is apparently closely associated with other IRF-7 splicing variants. IRF- 7C inhibits the function of IRF-7 in transcriptional regulation of IFN genes. These data suggest that EBV may use splicing variants of IRF-7 for its transformation process in two strategies: to use oncogenic properties of various IRF-7 splicing variants, but use one of its splicing variants (IRF-7C) to block the IFN-induction function of IRF-7 that is detrimental for viral transformation. The work provides a novel relation of host/virus interactions, and has expanded our knowledge about IRFs in EBV transformation

The interaction between KSHV RTA and cellular RBP-Jκ and their subsequent DNA binding are not sufficient for activation of RBP-Jκ

Kaposi’s sarcoma-associated herpesvirus (KSHV) replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. RTA activates promoters by several mechanisms. RTA can bind to sequences in viral promoters and activate transcription. In addition, RTA interacts with the cellular recombination signal sequence-binding protein-J kappa (RBP- Jκ), a transcriptional repressor, converts the repressor into an activator and activates viral promoters via RBP- Jκ. Because RBP- Jκ is required for RTA to activate lytic replication, it is important to understand how RTA cooperates with RBP- Jκ protein to activate KSHV lytic replication program. Previously, we identified an RTA mutant, RTA-K152E, which has a defect in its direct DNA-binding activity. In this report, the effect of the mutant RTA on KSHV activation via RBP- Jκ protein is examined. We demonstrate that RTA-K152E interacts with RBP- Jκ physically and the mutant RTA and RBP-Jκ complex binds to target DNA properly in vivo and in vitro. However, the complex of RTA-K152E and RBP- Jκ does not activate transcription. Furthermore, the RTA mutant (RTA-K12E) inhibits cellular Notch-mediated RBP- Jκ activation. These data collectively suggest that the complex between KSHV RTA and cellular RBP- Jκ and the subsequent DNA binding by the complex are not sufficient for the activation of RBP- Jκ protein. Other factor(s) whether additional cofactor(s) in the complex or the intrinsic conformation of RTA, are predicted to be required for the activation of RBP- Jκ protein by RTA

Intracellular Signaling Molecules Activated by Epstein-Barr Virus for Induction of Interferon Regulatory Factor 7

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) is the principal oncogenic protein in the EBV transformation process. LMP-1 induces the expression of interferon regulatory factor 7 (IRF-7) and activates IRF-7 protein by phosphorylation and nuclear translocation. LMP-1 is an integral membrane protein with two regions in its C terminus that initiate signaling processes, the C-terminal activator regions 1 (CTAR-1) and CTAR-2. Here, genetic analysis of LMP-1 has determined that the PXQXT motif that governs the interaction between LMP-1 CTAR-1 and tumor necrosis factor receptor-associated factors (TRAFs) is needed to induce the expression of IRF-7. Mutations in the PXQXT motif in CTAR-1 that disrupt the interaction between LMP-1 and TRAFs abolished the induction of IRF-7. Also, dominant-negative mutants of TRAFs inhibited the induction of IRF-7 by CTAR-1. The last three amino acids (YYD) of CTAR-2 are also important for the induction of IRF-7. When both PXQXT and YYD were mutated (LMP-DM), the LMP-1 mutant failed to induce IRF-7. Also, LMP-DM blocked the induction of IRF-7 by wild-type LMP-1. These data strongly suggest that both CTAR-1 and CTAR-2 of LMP-1 independently induce the expression of IRF-7. In addition, NF-_B is involved in the induction of IRF-7. A superrepressor of I_B (sr-I_B) could block the induction of IRF-7 by LMP-1, and overexpression of NF-_B (p65 plus p50) could induce the expression of IRF-7. In addition, we have found that human IRF-7 is a stable protein, and sodium butyrate, a modifier of chromatin structure, induces IRF-7

The interaction between KSHV RTA and cellular RBP-Jκ and their subsequent DNA binding are not sufficient for activation of RBP-Jκ

Kaposi’s sarcoma-associated herpesvirus (KSHV) replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. RTA activates promoters by several mechanisms. RTA can bind to sequences in viral promoters and activate transcription. In addition, RTA interacts with the cellular recombination signal sequence-binding protein-J kappa (RBP- Jκ), a transcriptional repressor, converts the repressor into an activator and activates viral promoters via RBP- Jκ. Because RBP- Jκ is required for RTA to activate lytic replication, it is important to understand how RTA cooperates with RBP- Jκ protein to activate KSHV lytic replication program. Previously, we identified an RTA mutant, RTA-K152E, which has a defect in its direct DNA-binding activity. In this report, the effect of the mutant RTA on KSHV activation via RBP- Jκ protein is examined. We demonstrate that RTA-K152E interacts with RBP- Jκ physically and the mutant RTA and RBP-Jκ complex binds to target DNA properly in vivo and in vitro. However, the complex of RTA-K152E and RBP- Jκ does not activate transcription. Furthermore, the RTA mutant (RTA-K12E) inhibits cellular Notch-mediated RBP- Jκ activation. These data collectively suggest that the complex between KSHV RTA and cellular RBP- Jκ and the subsequent DNA binding by the complex are not sufficient for the activation of RBP- Jκ protein. Other factor(s) whether additional cofactor(s) in the complex or the intrinsic conformation of RTA, are predicted to be required for the activation of RBP- Jκ protein by RTA

Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles

<p>Abstract</p> <p>Background</p> <p>Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD). While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC) differentiation by <it>tmem59 </it>is explored on the genome-level.</p> <p>Results</p> <p>We identified regulators of <it>tmem59 </it>during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred <it>tmem59 </it>related gene network including 36 genes, <it>pou6f1 </it>was identified to regulate <it>tmem59 </it>significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that <it>tmem59 </it>locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of <it>pou6f1 </it>could significantly up-regulate <it>tmem59 </it>expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including <it>Ace</it>, <it>aqp1</it>, <it>arrdc3</it>, <it>cd14</it>, <it>cd59a</it>, <it>cds1</it>, <it>cldn1</it>, <it>cox8b</it>, <it>defb11</it>, <it>folr1</it>, <it>gdi2</it>, <it>mmp3</it>, <it>mgp</it>, <it>myrip</it>, <it>Ripk4</it>, <it>rnd3</it>, and <it>sncg</it>. The localization of <it>tmem59 </it>related genes and functional-related gene groups based on the Gene Ontology (GO) annotation was also identified.</p> <p>Conclusions</p> <p>Our findings suggest that the expression of <it>tmem59 </it>is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to identifying genes for AD.</p

Interferon Regulatory Factor 4 (IRF-4) Targets IRF-5 to Regulate Epstein-Barr Virus Transformation

The cellular interferon regulatory factor-4 (IRF-4), which is a member of IRF family, is involved in the development of multiple myeloma and Epstein-Barr virus (EBV)-mediated transformation of B lymphocytes. However, the molecular mechanism of IRF-4 in cellular transformation is unknown. We have found that knockdown of IRF-4 leads to high expression of IRF-5, a pro-apoptotic member in the IRF family. Overexpression of IRF-4 represses IRF-5 expression. Reduction of IRF-4 leads to growth inhibition, and the restoration of IRF-4 by exogenous plasmids correlates with the growth recovery and reduces IRF-5 expression. In addition, IRF-4 negatively regulates IRF-5 promoter reporter activities and binds to IRF-5 promoters in vivo and in vitro. Knockdown of IRF-5 rescues IRF-4 knockdownmediated growth inhibition, and IRF-5 overexpression alone is sufficient to induce cellular growth inhibition of EBV-transformed cells. Therefore, IRF-5 is one of the targets of IRF-4, and IRF-4 regulates the growth of EBV-transformed cells partially through IRF-5. This work provides insight on how IRFs interact with one another to participate in viral pathogenesis and transformation