K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

Journal of Virology - Tập 89 Số 14 - Trang 7248-7261 - 2015
Lisa Steinbrück1, Montse Gustems1, Stephanie Medele1, Thomas F. Schulz2, Dominik Lutter3, Wolfgang Hammerschmidt1
1Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health and German Centre for Infection Research (DZIF) Partner Site, Munich, Germany
2Institute of Virology, Hanover Medical School, Hanover, Germany
3Institute of Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Garching, Germany

Tóm tắt

ABSTRACT The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodes LMP2A , one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genes K1 or K15 in lieu of LMP2A and infected primary BCR-negative (BCR − ) human B cells with them. We confirmed that the survival of BCR – B cells and their proliferation depended on an active LMP2A signal. Like LMP2A, the expression of K1 and K15 led to the survival of BCR − B cells prone to apoptosis, supported their proliferation, and regulated a similar set of cellular target genes. K1 and K15 encoded proteins appear to have noncomplementing, redundant functions in this model, but our findings suggest that both KSHV proteins can replace LMP2A's key activities contributing to the survival, activation and proliferation of BCR – PEL cells in vivo . IMPORTANCE Several herpesviruses encode oncogenes that are receptor-like proteins. Often, they are constitutively active providing important functions to the latently infected cells. LMP2A of Epstein-Barr virus (EBV) is such a receptor that mimics an activated B cell receptor, BCR. K1 and K15, related receptors of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in virus-associated tumors, have less obvious functions. We found in infection experiments that both viral receptors of KSHV can replace LMP2A and deliver functions similar to the endogenous BCR. K1, K15, and LMP2A also control the expression of a related set of cellular genes in primary human B cells, the target cells of EBV and KSHV. The observed phenotypes, as well as the known characteristics of these genes, argue for their contributions to cellular survival, B cell activation, and proliferation. Our findings provide one possible explanation for the tumorigenicity of KSHV, which poses a severe problem in immunocompromised patients.

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Tài liệu tham khảo

10.1038/nrc2542

10.1016/S0002-9440(10)65749-5

10.1002/ijc.21716

10.1182/blood-2007-05-090142

10.1002/j.1460-2075.1993.tb06205.x

10.1016/0960-9822(93)90196-U

10.1038/ni1036

10.1038/nri1201

10.1038/nrc1452

10.1182/blood.V90.3.1186.1186_1186_1191

Jenner RG, Boshoff C. 2002. The molecular pathology of Kaposi's sarcoma-associated herpesvirus. Biochim Biophys Acta 1602:1–22.

10.1182/blood.V88.7.2648.bloodjournal8872648

10.1038/sj.onc.1206270

10.1046/j.1365-2141.1998.00877.x

10.1182/blood.V87.12.4937.bloodjournal87124937

10.1016/j.canlet.2009.07.004

10.1128/JVI.00648-06

10.1038/nm0498-435

10.1093/jnci/94.12.926

10.1084/jem.192.1.11

10.1128/JVI.01696-09

10.1128/jvi.67.6.3087-3094.1993

10.1172/JCI58530

10.1172/JCI46499

10.1371/journal.ppat.1001063

10.1016/S0140-6736(64)92345-1

10.1093/emboj/21.5.954

10.1182/blood-2005-06-2341

10.1073/pnas.95.14.8245

10.1093/nar/gni035

10.1371/journal.ppat.1002704

10.1073/pnas.1115906109

10.1128/JVI.06314-11

Dirmeier U, Neuhierl B, Kilger E, Reisbach G, Sandberg ML, Hammerschmidt W. 2003. Latent membrane protein 1 is critical for efficient growth transformation of human B cells by Epstein-Barr virus. Cancer Res 63:2982–2989.

10.1093/bioinformatics/btg405

10.1186/gb-2004-5-10-r80

10.1038/nmeth757

10.1137/S0895479893259546

10.1182/blood-2005-06-2342

10.1182/blood-2005-06-2327

10.1128/JVI.74.1.436-446.2000

10.1073/pnas.232381299

10.1016/j.jbi.2009.01.002

10.1093/bioinformatics/btn245

10.1186/gb-2003-4-11-r76

10.1186/1471-2105-9-100

10.1093/bioinformatics/18.1.51

10.1371/journal.pbio.0030404

10.1016/j.ejcb.2011.01.014

10.1016/j.chom.2010.11.004

10.1038/sj.onc.1207905

10.1128/JVI.79.13.8655-8660.2005

10.1038/381751a0

10.1182/blood-2003-04-1018

10.1016/S1074-7613(95)80040-9

10.1084/jem.194.3.255

10.1128/JVI.78.4.1918-1927.2004

10.1016/j.cell.2009.08.041

10.1172/JCI44185

10.1016/j.virol.2010.12.036

10.1128/JVI.01587-07

10.1016/j.tim.2006.11.002

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Journal of Virology

Tập 89 Số 14

7248-7261

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