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J. Biol. Chem., Vol. 280, Issue 16, 16038-16044, April 22, 2005

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Nuclear and Mitochondrial Localization Signals Overlap within Bovine Herpesvirus 1 Tegument Protein VP22^*

Jun Zhu, Zhaohua Qiu, Christiane Wiese¶, Yohei Ishii, Jen Friedrichsen, Gireesh Rajashekara, and Gary A. Splitter||

From the Departments of Animal Health and Biomedical Sciences and Biochemistry, University of Wisconsin, Madison, Wisconsin 53706

VP22, a tegument protein of bovine herpesvirus 1, accumulates in the nucleus of infected and transiently transfected cells. Previous studies indicated a possible regulatory function of VP22 within nuclei, but how VP22 enters nuclei is unknown. Despite the abundance of basic residues within this protein, no classic nuclear localization signal (NLS) motif has been identified. To identify the signal directing nuclear accumulation, a series of truncations, internal deletions, and point mutations were constructed. Fluorescence microscopy of cells transfected with VP22 constructs indicated that a sequence of 103 residues is necessary and sufficient for nuclear localization. This NLS sequence is conformation-sensitive in contrast to a classical sequential NLS. Energy depletion assays and co-immunoprecipitation suggested that this NLS sequence also binds histone H4, resulting in nuclear retention of VP22. In addition, a mitochondrial targeting sequence was identified at the C-terminal 49 amino acids, which overlapped the sequence required for nuclear targeting. Our findings demonstrate the diversity of VP22 protein to localize within the cell and provide the opportunity for VP22 to direct cargo specifically to different subcellular compartments.

Received for publication, January 3, 2005 , and in revised form, January 31, 2005.

^* This work was supported by National Institutes of Health Grant R01-GM60986 and United States Department of Agriculture Grant 2002-35204-11645. 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.

^¶ Supported by National Science Foundation Grant MCB-0344723 and as a Kimmel Scholar by the Sidney Kimmel Foundation for Cancer Research.

^|| To whom correspondence should be addressed: Dept. of Animal Health and Biomedical Sciences, University of Wisconsin, 1656 Linden Dr., Madison, WI 53706. Tel.: 608-262-0359; Fax: 608-262-7420; E-mail: Splitter{at}svm.vetmed.wisc.edu.

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