Upregulation of Cellular Bcl-2 by the KSHV Encoded RTA Promotes Virion Production

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 9

PMID 21901143

Citations 13

Authors

Jianming Gao

Qiliang Cai

Jie Lu

Hem Chandra Jha

Erle S Robertson

Affiliations

Soon will be listed here.

Abstract

Apoptosis of virus infected cells can restrict or dampen full blown virus propagation and this can serve as a protective mechanism against virus infection. Consequently, viruses can also delay programmed cell death by enhancing the expression of anti-apoptotic proteins. Human Bcl-2 is expressed on the surface of the mitochondrial membrane and functions as the regulator of the delicate balance between cell survival and apoptosis. In this report, we showed that the replication and transcription activator (RTA) encoded by KSHV ORF 50, a key regulator for KSHV reactivation from latent to lytic infection, upregulates the mRNA and protein levels of Bcl-2 in 293 cells, and TPA-induced KSHV-infected cells. Further analysis revealed that upregulation of the cellular Bcl-2 promoter by RTA is dose-dependent and acts through targeting of the CCN(9)GG motifs within the Bcl-2 promoter. The Bcl-2 P2 but not the P1 promoter is primarily responsive to RTA. The results of ChIP confirmed the direct interaction of RTA protein with the CCN(9)GG motifs. Knockdown of cellular Bcl-2 by lentivirus-delivered small hairpin RNA (shRNA) resulted in increased cell apoptosis and decreased virion production in KSHV-infected cells. These findings provide an insight into another mechanism by which KSHV utilizes the intrinsic apoptosis signaling pathways for prolonging the survival of lytically infected host cells to allow for maximum production of virus progeny.

Citing Articles

Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

Morales A, Gumenick R, Genovese C, Jang Y, Ouedraogo A, Ibanez de Garayo M PLoS Pathog. 2024; 20(1):e1011881.

PMID: 38190392 PMC: 10898863. DOI: 10.1371/journal.ppat.1011881.

Contrasting roles for G-quadruplexes in regulating human Bcl-2 and virus homologues KSHV KS-Bcl-2 and EBV BHRF1.

Kumar S, Ramamurthy C, Choudhary D, Sekar A, Patra A, Bhavesh N Sci Rep. 2022; 12(1):5019.

PMID: 35322051 PMC: 8943185. DOI: 10.1038/s41598-022-08161-9.

Silencing of semaphorin 3C suppresses cell proliferation and migration in MCF-7 breast cancer cells.

Zhu X, Zhang X, Ye Z, Chen Y, Lv L, Zhang X Oncol Lett. 2017; 14(5):5913-5917.

PMID: 29113226 PMC: 5661468. DOI: 10.3892/ol.2017.6920.

The Modulation of Apoptotic Pathways by Gammaherpesviruses.

Banerjee S, Uppal T, Strahan R, Dabral P, Verma S Front Microbiol. 2016; 7:585.

PMID: 27199919 PMC: 4847483. DOI: 10.3389/fmicb.2016.00585.

Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.

Burrer C, Foight G, Keating A, Chan G Virus Res. 2015; 211:86-8.

PMID: 26456186 PMC: 4792251. DOI: 10.1016/j.virusres.2015.10.007.

References

Lukac D, Kirshner J, Ganem D . Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol. 1999; 73(11):9348-61. PMC: 112969. DOI: 10.1128/JVI.73.11.9348-9361.1999. View

Song M, Deng H, Sun R . Comparative study of regulation of RTA-responsive genes in Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. J Virol. 2003; 77(17):9451-62. PMC: 187374. DOI: 10.1128/jvi.77.17.9451-9462.2003. View

Cotter 2nd M, Robertson E . The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology. 1999; 264(2):254-64. DOI: 10.1006/viro.1999.9999. View

Song M, Li X, Brown H, Sun R . Characterization of interactions between RTA and the promoter of polyadenylated nuclear RNA in Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. J Virol. 2002; 76(10):5000-13. PMC: 136175. DOI: 10.1128/jvi.76.10.5000-5013.2002. View

Yu Y, Black J, Goldsmith C, Browning P, Bhalla K, Offermann M . Induction of human herpesvirus-8 DNA replication and transcription by butyrate and TPA in BCBL-1 cells. J Gen Virol. 1999; 80 ( Pt 1):83-90. DOI: 10.1099/0022-1317-80-1-83. View

Wang Y, Yuan Y . Essential role of RBP-Jkappa in activation of the K8 delayed-early promoter of Kaposi's sarcoma-associated herpesvirus by ORF50/RTA. Virology. 2006; 359(1):19-27. PMC: 1905837. DOI: 10.1016/j.virol.2006.09.032. View

Young R, Korsmeyer S . A negative regulatory element in the bcl-2 5'-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993; 13(6):3686-97. PMC: 359837. DOI: 10.1128/mcb.13.6.3686-3697.1993. View

Ballestas M, Chatis P, Kaye K . Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science. 1999; 284(5414):641-4. DOI: 10.1126/science.284.5414.641. View

Rimessi P, Bonaccorsi A, Sturzl M, Fabris M, Brocca-Cofano E, Caputo A . Transcription pattern of human herpesvirus 8 open reading frame K3 in primary effusion lymphoma and Kaposi's sarcoma. J Virol. 2001; 75(15):7161-74. PMC: 114445. DOI: 10.1128/JVI.75.15.7161-7174.2001. View

10.

Sakakibara S, Ueda K, Chen J, Okuno T, Yamanishi K . Octamer-binding sequence is a key element for the autoregulation of Kaposi's sarcoma-associated herpesvirus ORF50/Lyta gene expression. J Virol. 2001; 75(15):6894-900. PMC: 114417. DOI: 10.1128/JVI.75.15.6894-6900.2001. View

11.

Liu Y, Cao Y, Liang D, Gao Y, Xia T, Robertson E . Kaposi's sarcoma-associated herpesvirus RTA activates the processivity factor ORF59 through interaction with RBP-Jkappa and a cis-acting RTA responsive element. Virology. 2008; 380(2):264-75. PMC: 5868747. DOI: 10.1016/j.virol.2008.08.011. View

12.

Sharp T, Wang H, Koumi A, Hollyman D, Endo Y, Ye H . K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol. 2001; 76(2):802-16. PMC: 136811. DOI: 10.1128/jvi.76.2.802-816.2002. View

13.

Leiter U, Schmid R, Kaskel P, Peter R, Krahn G . Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res. 2000; 292(5):225-32. DOI: 10.1007/s004030050479. View

14.

Junn H, Kim J, Seol D . Effective knockdown of multiple target genes by expressing the single transcript harbouring multi-cistronic shRNAs. Biochem Biophys Res Commun. 2010; 396(4):861-5. DOI: 10.1016/j.bbrc.2010.05.008. View

15.

Boshoff C, Schulz T, Kennedy M, Graham A, Fisher C, Thomas A . Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995; 1(12):1274-8. DOI: 10.1038/nm1295-1274. View

16.

Lu J, Verma S, Murakami M, Cai Q, Kumar P, Xiao B . Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (KSHV) upregulates survivin expression in KSHV-Associated B-lymphoma cells and contributes to their proliferation. J Virol. 2009; 83(14):7129-41. PMC: 2704763. DOI: 10.1128/JVI.00397-09. View

17.

Wang S, Wu F, Fujimuro M, Zong J, Hayward S, Hayward G . Role of CCAAT/enhancer-binding protein alpha (C/EBPalpha) in activation of the Kaposi's sarcoma-associated herpesvirus (KSHV) lytic-cycle replication-associated protein (RAP) promoter in cooperation with the KSHV replication and transcription.... J Virol. 2002; 77(1):600-23. PMC: 140597. DOI: 10.1128/jvi.77.1.600-623.2003. View

18.

Brychtova S, Brychta T, Kotrsova L, Pilka R, Tichy M, Ticha V . Expression of Bcl-2 in dysplastic and neoplastic cervical lesions in relation to cell proliferation and HPV infection. Neoplasma. 2000; 47(3):143-7. View

19.

Soulier J, GROLLET L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P . Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995; 86(4):1276-80. View

20.

He Z, Liu Y, Liang D, Wang Z, Robertson E, Lan K . Cellular corepressor TLE2 inhibits replication-and-transcription- activator-mediated transactivation and lytic reactivation of Kaposi's sarcoma-associated herpesvirus. J Virol. 2009; 84(4):2047-62. PMC: 2812399. DOI: 10.1128/JVI.01984-09. View