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Journal of Virology, July 2001, p. 5891-5898, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5891-5898.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Immunoreceptor Tyrosine-Based Activation Motif-Dependent Signaling by Kaposi's Sarcoma-Associated Herpesvirus K1 Protein: Effects on Lytic Viral Replication

Michael Lagunoff,dagger David M. Lukac,Dagger and Don Ganem*

Howard Hughes Medical Institute, Departments of Microbiology and Immunology and Medicine, University of California Medical Center, San Francisco, California 94143-0414

Received 5 February 2001/Accepted 3 April 2001

The Kaposi's sarcoma-associated herpesvirus (KSHV) K1 gene encodes a polypeptide bearing an immunoreceptor tyrosine-based activation motif (ITAM) that is constitutively active for ITAM-based signal transduction. Although ectopic overexpression of K1 in cultured fibroblasts can lead to growth transformation, in vivo this gene is primarily expressed in lymphoid cells undergoing lytic infection. Here we have examined function of K1 in the setting of lytic replication, through the study of K1 mutants lacking functional ITAMs. Expression of such mutants in BJAB cells cotransfected with wild-type K1 results in dramatic inhibition of K1 signal transduction, as judged by impaired activation of Syk kinase and phospholipase C-gamma 2 as well as by diminished expression of a luciferase reporter gene dependent upon K1-induced calcium and Ras signaling. Thus, the mutants behave as dominantly acting inhibitors of K1 function. To assess the role of K1 in lytic replication, we introduced these K1 mutants into BCBL-1 cells, a B-cell lymphoma line latently infected with KSHV, and induced lytic replication by ectopic expression of the KSHV ORF50 transactivator. Expression of lytic cycle genes was diminished up to 80% in the presence of a K1 dominant negative mutant. These inhibitory effects could be overridden by tetradecanoyl phorbol acetate treatment, indicating that inhibition was not due to irreversible cell injury and suggesting that other signaling events could bypass the block. We conclude that ITAM-dependent signaling by K1 is not absolutely required for lytic reactivation but functions to modestly augment lytic replication in B cells, the natural reservoir of KSHV.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, School of Medicine, University of California, San Francisco, San Francisco, CA 94143-0414. Phone: (415) 476-2826. Fax: (415) 476-0939. E-mail: ganem{at}cgl.ucsf.edu.

dagger Present address: Department of Microbiology, University of Washington, Seattle, WA 98195.

Dagger Present address: Department of Microbiology and Molecular Genetics, UMDNJ/NJ Medical School, Newark, NJ 07103.

Journal of Virology, July 2001, p. 5891-5898, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5891-5898.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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