Kaposi's sarcoma-associated herpesvirus Lana-1 is a major activator of the serum response element and mitogen-activated protein kinase pathways via interactions with the Mediator complex
In cells infected with Kaposi's sarcoma-associated herpesvirus (KSHV), the activation of mitogen-activated protein kinase (MAPK) pathways plays a crucial role early after virus infection as well as during reactivation. In order to systematically identify viral proteins activating MAPK pathways in KSHV-infected cells, a clone collection of KSHV open reading frames (ORFs) was screened for induction of the serum response element (SRE), as SRE is induced by MAPKs. The strongest induction of the SRE was found with ORF73 (latency-associated nuclear antigen 1, or Lana-1), although weaker activation was also found with the kaposin B isoform, ORF54 (dUTPase) and ORF74 (G-protein-coupled receptor). The bipartite SRE is bound by a ternary complex consisting of serum response factor (SRF) and ternary complex factor. Lana-1 bound directly to SRF, but also to the MED25 (ARC92/ACID-1), MED15 (PCQAP) and MED23 (Sur-2) subunits of the Mediator complex, a multi-subunit transcriptional co-activator complex for RNA polymerase II. Lana-1-induced SRE activation was inhibited by the dominant-negative N-terminal domain of the MED25 mediator subunit, suggesting that this subunit mediates Lana-1-induced SRE activation. In summary, these data suggest a model in which Lana-1 acts as an adaptor between the transcription factor SRF and the basal transcriptional machinery.
Angel, P. & Karin, M.(1991). The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta1072, 129–157.
[Google Scholar]
Arvanitakis, L., Geras, R. E., Varma, A., Gershengorn, M. C. & Cesarman, E.(1997). Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature385, 347–350.[CrossRef][Google Scholar]
Barbera, A. J., Chodaparambil, J. V., Kelley-Clarke, B., Joukov, V., Walter, J. C., Luger, K. & Kaye, K. M.(2006). The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science311, 856–861.[CrossRef][Google Scholar]
Bourbon, H. M., Aguilera, A., Ansari, A. Z., Asturias, F. J., Berk, A. J., Bjorklund, S., Blackwell, T. K., Borggrefe, T., Carey, M. & other authors(2004). A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II. Mol Cell14, 553–557.[CrossRef][Google Scholar]
Casamassimi, A. & Napoli, C.(2007). Mediator complexes and eukaryotic transcription regulation: an overview. Biochimie89, 1439–1446.[CrossRef][Google Scholar]
Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M.(1995). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med332, 1186–1191. (see comments)[CrossRef][Google Scholar]
Chai, J. & Tarnawski, A. S.(2002). Serum response factor: discovery, biochemistry, biological roles and implications for tissue injury healing. J Physiol Pharmacol53, 147–157.
[Google Scholar]
Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M. & Moore, P. S.(1994). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science266, 1865–1869.[CrossRef][Google Scholar]
Dupin, N., Fisher, C., Kellam, P., Ariad, S., Tulliez, M., Franck, N., van Marck, E., Salmon, D., Gorin, I. & other authors(1999). Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A96, 4546–4551.[CrossRef][Google Scholar]
Ford, P. W., Bryan, B. A., Dyson, O. F., Weidner, D. A., Chintalgattu, V. & Akula, S. M.(2006). Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency. J Gen Virol87, 1139–1144.[CrossRef][Google Scholar]
Glaser, R., Litsky, M. L., Padgett, D. A., Baiocchi, R. A., Yang, E. V., Chen, M., Yeh, P. E., Green-Church, K. B., Caligiuri, M. A. & Williams, M. V.(2006). EBV-encoded dUTPase induces immune dysregulation: implications for the pathophysiology of EBV-associated disease. Virology346, 205–218.[CrossRef][Google Scholar]
Hong, Y. K., Foreman, K., Shin, J. W., Hirakawa, S., Curry, C. L., Sage, D. R., Libermann, T., Dezube, B. J., Fingeroth, J. D. & Detmar, M.(2004). Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet36, 683–685.[CrossRef][Google Scholar]
Katano, H., Sato, Y., Kurata, T., Mori, S. & Sata, T.(2000). Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman's disease. Virology269, 335–344.[CrossRef][Google Scholar]
Kellam, P., Boshoff, C., Whitby, D., Matthews, S., Weiss, R. A. & Talbot, S. J.(1997). Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome. J Hum Virol1, 19–29.
[Google Scholar]
Kovary, K. & Bravo, R.(1991). The Jun and Fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol11, 4466–4472.
[Google Scholar]
Kremmer, E., Sommer, P., Holzer, D., Galetsky, S. A., Molochkov, V. A., Gurtsevitch, V., Winkelmann, C., Lisner, R., Niedobitek, G. & Grasser, F. A.(1999). Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) ORF54 encodes a functional dUTPase expressed in the lytic replication cycle. J Gen Virol80, 1305–1310.
[Google Scholar]
Krithivas, A., Young, D. B., Liao, G., Greene, D. & Hayward, S. D.(2000). Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein–Barr virus gene expression in dually infected PEL cells. J Virol74, 9637–9645.[CrossRef][Google Scholar]
Lan, K., Kuppers, D. A., Verma, S. C. & Robertson, E. S.(2004). Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency. J Virol78, 6585–6594.[CrossRef][Google Scholar]
Lazo, P. S., Dorfman, K., Noguchi, T., Mattei, M. G. & Bravo, R.(1992). Structure and mapping of the fosB gene. FosB downregulates the activity of the fosB promoter. Nucleic Acids Res20, 343–350.[CrossRef][Google Scholar]
Liao, J., Hodge, C., Meyer, D., Ho, P. S., Rosenspire, K. & Schwartz, J.(1997). Growth hormone regulates ternary complex factors and serum response factor associated with the c-fos serum response element. J Biol Chem272, 25951–25958.[CrossRef][Google Scholar]
Lim, C., Sohn, H., Gwack, Y. & Choe, J.(2000). Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. J Gen Virol81, 2645–2652.
[Google Scholar]
Lim, C., Gwack, Y., Hwang, S., Kim, S. & Choe, J.(2001). The transcriptional activity of cAMP response element-binding protein-binding protein is modulated by the latency associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Biol Chem276, 31016–31022.[CrossRef][Google Scholar]
Liu, J., Martin, H. J., Liao, G. & Hayward, S. D.(2007). The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol81, 10451–10459.[CrossRef][Google Scholar]
McCormick, C. & Ganem, D.(2005). The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science307, 739–741.[CrossRef][Google Scholar]
Mittler, G., Stuhler, T., Santolin, L., Uhlmann, T., Kremmer, E., Lottspeich, F., Berti, L. & Meisterernst, M.(2003). A novel docking site on Mediator is critical for activation by VP16 in mammalian cells. EMBO J22, 6494–6504.[CrossRef][Google Scholar]
Montaner, S., Sodhi, A., Molinolo, A., Bugge, T. H., Sawai, E. T., He, Y., Li, Y., Ray, P. E. & Gutkind, J. S.(2003). Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell3, 23–36.[CrossRef][Google Scholar]
Naranatt, P. P., Akula, S. M., Zien, C. A., Krishnan, H. H. & Chandran, B.(2003). Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-ζ-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol77, 1524–1539.[CrossRef][Google Scholar]
Pan, H., Xie, J., Ye, F. & Gao, S. J.(2006). Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol80, 5371–5382.[CrossRef][Google Scholar]
Platt, G. M., Simpson, G. R., Mittnacht, S. & Schulz, T. F.(1999). Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene. J Virol73, 9789–9795.
[Google Scholar]
Posern, G. & Treisman, R.(2006). Actin' together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol16, 588–596.[CrossRef][Google Scholar]
Rainbow, L., Platt, G. M., Simpson, G. R., Sarid, R., Gao, S. J., Stoiber, H., Herrington, C. S., Moore, P. S. & Schulz, T. F.(1997). The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen. J Virol71, 5915–5921.
[Google Scholar]
Renne, R., Barry, C., Dittmer, D., Compitello, N., Brown, P. O. & Ganem, D.(2001). Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol75, 458–468.[CrossRef][Google Scholar]
Rovnak, J. & Quackenbush, S. L.(2002). Walleye dermal sarcoma virus cyclin interacts with components of the mediator complex and the RNA polymerase II holoenzyme. J Virol76, 8031–8039.[CrossRef][Google Scholar]
Schwarz, M. & Murphy, P. M.(2001). Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-κB and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol167, 505–513.[CrossRef][Google Scholar]
Sharma-Walia, N., Krishnan, H. H., Naranatt, P. P., Zeng, L., Smith, M. S. & Chandran, B.(2005). ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol79, 10308–10329.[CrossRef][Google Scholar]
Shaw, P. E. & Saxton, J.(2003). Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases. Int J Biochem Cell Biol35, 1210–1226.[CrossRef][Google Scholar]
Smit, M. J., Verzijl, D., Casarosa, P., Navis, M., Timmerman, H. & Leurs, R.(2002). Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via Gi and phospholipase C-dependent signaling pathways. J Virol76, 1744–1752.[CrossRef][Google Scholar]
Soulier, J., Grollet, L., Oksenhendler, E., Cacoub, P., Cazals-Hatem, D., Babinet, P., d'Agay, M. F., Clauvel, J. P., Raphael, M. & other authors(1995). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood86, 1276–1280.
[Google Scholar]
Stevens, J. L., Cantin, G. T., Wang, G., Shevchenko, A., Shevchenko, A. & Berk, A. J.(2002). Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science296, 755–758.[CrossRef][Google Scholar]
Subramani, S., Mulligan, R. & Berg, P.(1981). Expression of the mouse dihydrofolate reductase complementary deoxyribonucleic acid in simian virus 40 vectors. Mol Cell Biol1, 854–864.
[Google Scholar]
Treisman, R.(1986). Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell46, 567–574.[CrossRef][Google Scholar]
Uetz, P., Dong, Y. A., Zeretzke, C., Atzler, C., Baiker, A., Berger, B., Rajagopala, S. V., Roupelieva, M., Rose, D. & other authors(2006). Herpesviral protein networks and their interaction with the human proteome. Science311, 239–242.[CrossRef][Google Scholar]
Viejo-Borbolla, A., Kati, E., Sheldon, J. A., Nathan, K., Mattsson, K., Szekely, L. & Schulz, T. F.(2003). A domain in the C-terminal region of latency-associated nuclear antigen 1 of Kaposi's sarcoma-associated herpesvirus affects transcriptional activation and binding to nuclear heterochromatin. J Virol77, 7093–7100.[CrossRef][Google Scholar]
Wang, G. & Berk, A. J.(2002). In vivo association of adenovirus large E1A protein with the human mediator complex in adenovirus-infected and -transformed cells. J Virol76, 9186–9193.[CrossRef][Google Scholar]
Wang, H. W., Trotter, M. W., Lagos, D., Bourboulia, D., Henderson, S., Makinen, T., Elliman, S., Flanagan, A. M., Alitalo, K. & Boshoff, C.(2004). Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet36, 687–693.[CrossRef][Google Scholar]
Winter, H. Y. & Marriott, S. J.(2007). Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol81, 6089–6098.[CrossRef][Google Scholar]
Xie, J., Ajibade, A. O., Ye, F., Kuhne, K. & Gao, S. J.(2008). Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways. Virology371, 139–154.[CrossRef][Google Scholar]
Yang, M., Hay, J. & Ruyechan, W. T.(2008). Varicella-zoster virus IE62 protein utilizes the human mediator complex in promoter activation. J Virol82, 12154–12163.[CrossRef][Google Scholar]
Yu, F., Harada, J. N., Brown, H. J., Deng, H., Song, M. J., Wu, T. T., Kato-Stankiewicz, J., Nelson, C. G., Vieira, J. & other authors(2007). Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus. PLoS Pathog3, e44[CrossRef][Google Scholar]
Kaposi's sarcoma-associated herpesvirus Lana-1 is a major activator of the serum response element and mitogen-activated protein kinase pathways via interactions with the Mediator complex