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J. Biol. Chem., Vol. 280, Issue 7, 5902-5908, February 18, 2005

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Histone Acetylase GCN5 Enters the Nucleus via Importin- in Protozoan Parasite Toxoplasma gondii^*

Micah M. Bhatti and William J. Sullivan, Jr.

From the Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202

The histone acetyltransferase GCN5 acetylates nucleosomal histones to alter gene expression. How GCN5 gains entry into the nucleus of the cell has not been determined. We have mapped a six-amino acid motif (RKRVKR) that serves as a necessary and sufficient nuclear localization signal (NLS) for GCN5 in the protozoan pathogen Toxoplasma gondii (TgGCN5). Virtually nothing is known about nucleocytoplasmic transport in these parasites (phylum Apicomplexa), and this study marks the first demonstrated NLS delineated for members of the phylum. The TgGCN5 NLS has predictive value because it successfully identifies other nuclear proteins in three different apicomplexan genomic databases. Given the basic composition of the T. gondii NLS, we hypothesized that TgGCN5 physically interacts with importin-, the main transport receptor in the importin/karyopherin nuclear import pathway. We cloned the importin- gene from T. gondii (TgIMP), which encodes a protein of 545 amino acids that possesses an importin--binding domain and armadillo/-catenin-like repeats. In vitro co-immunoprecipitation experiments confirm that TgIMP directly interacts with TgGCN5, but this interaction is abolished if the TgGCN5 NLS is deleted. Taken together, these data argue that TgGCN5 gains access to the parasite nucleus by interacting with TgIMP. Bioinformatics analysis of the T. gondii genome reveals that other components of the importin pathway are present in the organism. This study demonstrates the utility of T. gondii as a model for the study of nucleocytoplasmic trafficking in early eukaryotic cells.

Received for publication, September 16, 2004 , and in revised form, December 7, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY267540.

^* This work was supported by National Institutes of Health Grant GM065051 and a Biomedical Research grant from Indiana University School of Medicine (to W. J. S.). 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 material.

To whom correspondence should be addressed: Dept. of Pharmacology & Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., MS A-525, Indianapolis, IN 46202. Tel.: 317-274-1573; Fax: 317-274-7714; E-mail: wjsulliv{at}iupui.edu.

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