This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsai, Y.-H.
Right arrow Articles by Wang, H.-W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsai, Y.-H.
Right arrow Articles by Wang, H.-W.

 Previous Article  |  Next Article 

Journal of Virology, January 2009, p. 622-632, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.00869-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The M Type K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus Regulates MicroRNA Expression via Its SH2-Binding Motif To Induce Cell Migration and Invasion{triangledown}

Yuan-Hau Tsai,1,{dagger} Min-Fen Wu,1,{dagger} Yu-Hsuan Wu,1 Shing-Jyh Chang,4 Su-Fang Lin,5 Tyson V. Sharp,6 and Hsei-Wei Wang1,2,3*

Institutes of Microbiology and Immunology,1 Clinical Medicine,2 National Yang-Ming University, Department of Teaching and Research, Taipei City Hospital,3 Department of Obstetrics and Gynecology, Hsin-Chu Mackay Memorial Hospital,4 Division of Clinical Research, National Health Research Institute, Taipei, Taiwan,5 School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom6

Received 24 April 2008/ Accepted 20 October 2008

Kaposi's sarcoma (KS) associated herpesvirus (KSHV) is the etiological agent of KS. In vivo, KS is a tumor capable of spreading throughout the body, and pulmonary metastasis is observed clinically. In vitro, KSHV induces the invasiveness of endothelial cells. The KSHV open reading frame K15 is a KSHV-specific gene encoding a transmembrane protein. Two highly divergent forms of K15, the predominant (P) and minor (M) forms (K15P and K15M, respectively), have been identified in different KSHV strains. The two K15 alleles resemble the latent membrane protein 2A (LMP2A) gene of Epstein-Barr virus (EBV) in their genomic locations and protein topology. Also, both K15 proteins have motifs similar to those found in the EBV LMP1 protein. K15 therefore appears to be a hybrid of a distant evolutionary relative of EBV LMP1 and LMP2A. Since both LMP1 and LMP2A proteins are capable of inducing cell motility, we sought to determine whether K15 has similar abilities. In this study, we show that K15M is latently expressed in KSHV-positive PEL cells and knockdown of K15M in PEL cells reduces cell motility. K15M localizes to lysosomal membranes and induces cell migration, invasion, and NF-{kappa}B (but not AP-1) activity via its conserved SH2-binding motif. K15M also induces the expression of microRNAs miR-21 and miR-31 via this conserved motif, and knocking down both these microRNAs eliminates K15M-induced cell motility. Therefore, K15M may contribute to KSHV-mediated tumor metastasis and angiogenesis via regulation of miR-21 and miR-31, which we show here for the first time to be a specific regulator of cell migration. In light of these findings, the targeting of K15 or the downstream microRNAs regulated by it may represent novel therapies for treatment of KSHV-associated neoplasia.

* Corresponding author. Mailing address: Institute of Microbiology and Immunology, National Yang-Ming University, No. 155, Sec 2, Li-Nong Street, Taipei 112, Taiwan. Phone: 886-2-2826-7109. Fax: 886-2-2821-2880. E-mail: hwwang{at}ym.edu.tw

{triangledown} Published ahead of print on 29 October 2008.

{dagger} Y.-H.T. and M.-F.W. contributed equally to this study.

Journal of Virology, January 2009, p. 622-632, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.00869-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»