Mitogen and Stress Activated Kinases Act Co-operatively with CREB during the Induction of Human Cytomegalovirus Immediate-Early Gene Expression from Latency
The devastating clinical consequences associated with human cytomegalovirus (HCMV) infection and reactivation underscores the importance of understanding triggers of HCMV reactivation in dendritic cells (DC). Here we show that ERK-mediated reactivation is dependent on the mitogen and stress activated kinase (MSK) family. Furthermore, this MSK mediated response is dependent on CREB binding to the viral major immediate early promoter (MIEP). Specifically, CREB binding to the MIEP provides the target for MSK recruitment. Importantly, MSK mediated phosphorylation of histone H3 is required to promote histone de-methylation and the subsequent exit of HCMV from latency. Taken together, these data suggest that CREB binding to the MIEP is necessary for the recruitment of the kinase activity of MSKs to initiate the chromatin remodelling at the MIEP required for reactivation. Thus the importance of CREB during HCMV reactivation is to promote chromatin modifications conducive for viral gene expression as well as acting as a classical transcription factor. Clearly, specific inhibition of this interaction between CREB and MSKs could provide a strategy for therapeutic intervention.
References
[1]
Sinclair J, Sissons P (2006) Latency and reactivation of human cytomegalovirus. J Gen Virol 87: 1763–1779.
[2]
Peggs KS, Mackinnon S (2004) Cytomegalovirus: the role of CMV post-haematopoietic stem cell transplantation. Int J Biochem Cell Biol 36: 695–701.
[3]
Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, et al. (2008) Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 300: 413–422.
[4]
Legendre C, Pascual M (2008) Improving outcomes for solid-organ transplant recipients at risk from cytomegalovirus infection: late-onset disease and indirect consequences. Clin Infect Dis 46: 732–740.
[5]
Mendelson M, Monard S, Sissons P, Sinclair J (1996) Detection of endogenous human cytomegalovirus in CD34+ bone marrow progenitors. J Gen Virol 77 (Pt 12) 3099–3102.
[6]
Zhuravskaya T, Maciejewski JP, Netski DM, Bruening E, Mackintosh FR, et al. (1997) Spread of human cytomegalovirus (HCMV) after infection of human hematopoietic progenitor cells: model of HCMV latency. Blood 90: 2482–2491.
[7]
Goodrum FD, Jordan CT, High K, Shenk T (2002) Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc Natl Acad Sci U S A 99: 16255–16260.
[8]
Hahn G, Jores R, Mocarski ES (1998) Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci U S A 95: 3937–3942.
[9]
Sindre H, Tjoonnfjord GE, Rollag H, Ranneberg-Nilsen T, Veiby OP, et al. (1996) Human cytomegalovirus suppression of and latency in early hematopoietic progenitor cells. Blood 88: 4526–4533.
[10]
Slobedman B, Mocarski ES (1999) Quantitative analysis of latent human cytomegalovirus. J Virol 73: 4806–4812.
[11]
Taylor-Wiedeman J, Sissons JG, Borysiewicz LK, Sinclair JH (1991) Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72 (Pt 9) 2059–2064.
[12]
Bevan IS, Daw RA, Day PJ, Ala FA, Walker MR (1991) Polymerase chain reaction for detection of human cytomegalovirus infection in a blood donor population. Br J Haematol 78: 94–99.
[13]
Reeves MB, Compton T (2011) Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J Virol 85: 12750–12758.
[14]
Taylor-Wiedeman J, Sissons P, Sinclair J (1994) Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol 68: 1597–1604.
[15]
Reeves MB, MacAry PA, Lehner PJ, Sissons JG, Sinclair JH (2005) Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A 102: 4140–4145.
[16]
Huang MM, Kew VG, Jestice K, Wills MR, Reeves MB (2012) Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can be studied using a CD14+ experimental latency model. J Virol 86: 8507–8515.
[17]
Hargett D, Shenk TE (2010) Experimental human cytomegalovirus latency in CD14+ monocytes. Proc Natl Acad Sci U S A 107: 20039–20044.
[18]
Soderberg-Naucler C, Fish KN, Nelson JA (1997) Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91: 119–126.
[19]
Yuan J, Liu X, Wu AW, McGonagill PW, Keller MJ, et al. (2009) Breaking human cytomegalovirus major immediate-early gene silence by vasoactive intestinal peptide stimulation of the protein kinase A-CREB-TORC2 signaling cascade in human pluripotent embryonal NTera2 cells. J Virol 83: 6391–6403.
[20]
Keller MJ, Wu AW, Andrews JI, McGonagill PW, Tibesar EE, et al. (2007) Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway. J Virol 81: 6669–6681.
[21]
Keller MJ, Wheeler DG, Cooper E, Meier JL (2003) Role of the human cytomegalovirus major immediate-early promoter's 19-base-pair-repeat cyclic AMP-response element in acutely infected cells. J Virol 77: 6666–6675.
[22]
Prosch S, Wuttke R, Kruger DH, Volk HD (2002) NF-kappaB–a potential therapeutic target for inhibition of human cytomegalovirus (re)activation? Biol Chem 383: 1601–1609.
[23]
Hummel M, Kurian SM, Lin S, Borodyanskiy A, Zhang Z, et al. (2009) Intragraft TNF receptor signaling contributes to activation of innate and adaptive immunity in a renal allograft model. Transplantation 87: 178–188.
[24]
Hummel M, Abecassis MM (2002) A model for reactivation of CMV from latency. J Clin Virol 25 Suppl 2: S123–136.
[25]
Cook CH, Trgovcich J, Zimmerman PD, Zhang Y, Sedmak DD (2006) Lipopolysaccharide, tumor necrosis factor alpha, or interleukin-1beta triggers reactivation of latent cytomegalovirus in immunocompetent mice. J Virol 80: 9151–9158.
[26]
Liu X, Yuan J, Wu AW, McGonagill PW, Galle CS, et al. (2010) Phorbol ester-induced human cytomegalovirus major immediate-early (MIE) enhancer activation through PKC-delta, CREB, and NF-kappaB desilences MIE gene expression in quiescently infected human pluripotent NTera2 cells. J Virol 84: 8495–8508.
[27]
O'Connor CM, Murphy EA (2012) A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J Virol 86: 9854–9865.
[28]
Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5: 875–885.
[29]
Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26: 3279–3290.
[30]
Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, et al. (1996) Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J 15: 817–826.
[31]
Banerjee A, Gugasyan R, McMahon M, Gerondakis S (2006) Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc Natl Acad Sci U S A 103: 3274–3279.
[32]
Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, et al. (2000) TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103: 1071–1083.
[33]
Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513: 1–13.
[34]
Deak M, Clifton AD, Lucocq LM, Alessi DR (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17: 4426–4441.
[35]
Romeo Y, Zhang X, Roux PP (2012) Regulation and function of the RSK family of protein kinases. Biochem J 441: 553–569.
[36]
Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P (1998) Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK. J Biol Chem 273: 1496–1505.
[37]
Arthur JS (2008) MSK activation and physiological roles. Front Biosci 13: 5866–5879.
[38]
Murphy JC, Fischle W, Verdin E, Sinclair JH (2002) Control of cytomegalovirus lytic gene expression by histone acetylation. EMBO J 21: 1112–1120.
[39]
Lashmit P, Wang S, Li H, Isomura H, Stinski MF (2009) The CREB site in the proximal enhancer is critical for cooperative interaction with the other transcription factor binding sites to enhance transcription of the major intermediate-early genes in human cytomegalovirus-infected cells. J Virol 83: 8893–8904.
[40]
Meier JL, Stinski MF (1996) Regulation of human cytomegalovirus immediate-early gene expression. Intervirology 39: 331–342.
[41]
Arthur JS, Cohen P (2000) MSK1 is required for CREB phosphorylation in response to mitogens in mouse embryonic stem cells. FEBS Lett 482: 44–48.
[42]
Deeble PD, Murphy DJ, Parsons SJ, Cox ME (2001) Interleukin-6- and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. Mol Cell Biol 21: 8471–8482.
[43]
Cox ME, Deeble PD, Bissonette EA, Parsons SJ (2000) Activated 3′,5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J Biol Chem 275: 13812–13818.
[44]
Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, et al. (2003) MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J 22: 2788–2797.
[45]
Mahadevan LC, Willis AC, Barratt MJ (1991) Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell 65: 775–783.
[46]
Barratt MJ, Hazzalin CA, Cano E, Mahadevan LC (1994) Mitogen-stimulated phosphorylation of histone H3 is targeted to a small hyperacetylation-sensitive fraction. Proc Natl Acad Sci U S A 91: 4781–4785.
[47]
Cha-Molstad H, Keller DM, Yochum GS, Impey S, Goodman RH (2004) Cell-type-specific binding of the transcription factor CREB to the cAMP-response element. Proc Natl Acad Sci U S A 101: 13572–13577.
[48]
Weekes MP, Tan SY, Poole E, Talbot S, Antrobus R, et al. (2013) Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340: 199–202.
[49]
Teng MW, Bolovan-Fritts C, Dar RD, Womack A, Simpson ML, et al. (2013) An endogenous accelerator for viral gene expression confers a fitness advantage. Cell 151: 1569–1580.
[50]
Cinatl J Jr, Margraf S, Vogel JU, Scholz M, Cinatl J, et al. (2001) Human cytomegalovirus circumvents NF-kappa B dependence in retinal pigment epithelial cells. J Immunol 167: 1900–1908.
[51]
Cheung P, Tanner KG, Cheung WL, Sassone-Corsi P, Denu JM, et al. (2000) Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol Cell 5: 905–915.
[52]
Wei Y, Yu L, Bowen J, Gorovsky MA, Allis CD (1999) Phosphorylation of histone H3 is required for proper chromosome condensation and segregation. Cell 97: 99–109.
[53]
Vicent GP, Ballare C, Nacht AS, Clausell J, Subtil-Rodriguez A, et al. (2006) Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Mol Cell 24: 367–381.
[54]
Shimada M, Nakadai T, Fukuda A, Hisatake K (2010) cAMP-response element-binding protein (CREB) controls MSK1-mediated phosphorylation of histone H3 at the c-fos promoter in vitro. J Biol Chem 285: 9390–9401.
[55]
Song MJ, Hwang S, Wong W, Round J, Martinez-Guzman D, et al. (2004) The DNA architectural protein HMGB1 facilitates RTA-mediated viral gene expression in gamma-2 herpesviruses. J Virol 78: 12940–12950.
[56]
Harrison SM, Whitehouse A (2008) Kaposi's sarcoma-associated herpesvirus (KSHV) Rta and cellular HMGB1 proteins synergistically transactivate the KSHV ORF50 promoter. FEBS Lett 582: 3080–3084.
[57]
Vermeulen L, Vanden Berghe W, Beck IM, De Bosscher K, Haegeman G (2009) The versatile role of MSKs in transcriptional regulation. Trends Biochem Sci 34: 311–318.
[58]
Compton T (2000) Analysis of cytomegalovirus ligands,, receptors, and the entry pathway. In: Sinclair J, editor. Methods in Molecular Medicine: Cytomegalovirus Protocols: Humana Press. 53–65 p.
[59]
Caposio P, Luganini A, Hahn G, Landolfo S, Gribaudo G (2007) Activation of the virus-induced IKK/NF-kappaB signalling axis is critical for the replication of human cytomegalovirus in quiescent cells. Cell Microbiol 9: 2040–2054.
[60]
Grassi F, Dezutter-Dambuyant C, McIlroy D, Jacquet C, Yoneda K, et al. (1998) Monocyte-derived dendritic cells have a phenotype comparable to that of dermal dendritic cells and display ultrastructural granules distinct from Birbeck granules. J Leukoc Biol 64: 484–493.
