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J. Biol. Chem., Vol. 282, Issue 47, 34581-34593, November 23, 2007

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Identification of Human T Cell Leukemia Virus Type 1 Tax Amino Acid Signals and Cellular Factors Involved in Secretion of the Viral Oncoprotein^*

Pooja Jain¹, Kate Mostoller, Katherine E. Flaig, Jaya Ahuja, Veronique Lepoutre, Timothy Alefantis^¶, Zafar K. Khan, and Brian Wigdahl²

From the Department of Microbiology and Immunology, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, the Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, and ^¶Vital Probes, Inc., Mayfield, Pennsylvania 18433

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a number of pathologic abnormalities, including adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The viral oncoprotein Tax has been implicated in the pathogenesis of these diseases. Recently, cell-free Tax was detected in the cerebrospinal fluid of HAM/TSP patients, implying that extracellular Tax may be relevant to neurologic disease. Additionally, the presence of a nuclear export signal within Tax and its active secretion has been demonstrated in vitro. However, the mechanism of Tax secretion remains to be established. Studies reported herein elucidate the process of Tax secretion and identify domains of Tax critical to its subcellular localization and secretion. Tax was shown to interact with a number of cellular secretory pathway proteins in both the model cell line BHK (baby hamster kidney)-21 and an HTLV-1-infected T cell line, C8166, physiologically relevant to HTLV-1-induced disease. Silencing of selected components of the secretory pathway affected Tax secretion, further confirming regulated secretion of Tax. Additionally, mutations in two putative secretory signals within Tax DHE and YTNI resulted in aberrant subcellular localization of Tax and significantly altered protein secretion. Together, these studies demonstrate that Tax secretion is a regulated event facilitated by its interactions with proteins of the cellular secretory pathway and the presence of secretory signals within the carboxyl-terminal domain of the protein.

Received for publication, August 30, 2007

^* These studies were supported in part by United States Public Heath Service/National Institutes of Health (USPHS/NIH) Grant 2R01 CA054559-13A1 (to B. W.) and USPHS/NIH Grant NS044801 (to K. M.). These studies were also supported by funding provided by the Pennsylvania State University College of Medicine Tobacco Settlement Block Grant under the Department of Health's Health Research Formula Funding Program (State of Pennsylvania, Act 2001-77, part of the Pennsylvania Tobacco Settlement Legislation). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported in part by CA054559 and by faculty development funds provided by the Department of Microbiology and Immunology of the Drexel University College of Medicine.

² To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Ln., Philadelphia, PA 19129. Tel.: 215-991-8352; Fax: 215-848-2271; E-mail: bwigdahl{at}drexelmed.edu.

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