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J. Biol. Chem., Vol. 278, Issue 42, 41198-41204, October 17, 2003

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A Novel Nuclear Localization Signal in the Auxiliary Domain of Apobec-1 Complementation Factor Regulates Nucleocytoplasmic Import and Shuttling^*

Valerie Blanc , Susan Kennedy  and Nicholas O. Davidson   ¶

From the Departments of Internal Medicine and Pharmacology and Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110

C to U editing of the nuclear apolipoprotein B (apoB) transcript is mediated by a core enzyme containing a catalytic deaminase, apobec-1, and an RNA binding subunit, apobec-1 complementation factor (ACF). ACF expression is predominantly nuclear, including mutant proteins with deletions of a putative nuclear localization signal. We have now identified a novel 41-residue motif (ANS) in the auxiliary domain of ACF that functions as an authentic nuclear localization signal. ANS-green fluorescence protein and ANS--galactosidase chimeras were both expressed exclusively in the nucleus, whereas wild-type chimeras or an ACF deletion mutant lacking the ANS were cytoplasmic. Nuclear accumulation of ACF is transcription-dependent, temperature-sensitive, and reversible, features reminiscent of a shuttling protein. ACF relocates to the cytoplasm after actinomycin D treatment, an effect blocked by the CRM1 inhibitor leptomycin B. Heterokaryon assays confirmed directly that ACF shuttles in vivo. ACF binds to the protein carrier, transportin 2 in vivo, and colocalizes to the nucleus as determined by confocal microscopy. Co-immunoprecipitation experiments revealed that transportin 2 binds directly to the ANS motif. These data suggest that directed nuclear localization and compartmentalization of the core complex of the apoB RNA editing enzyme is regulated through a dominant targeting sequence (ANS) contained within ACF.

Received for publication, March 23, 2003 , and in revised form, July 21, 2003.

^* This work was supported by National Institutes of Health Grants HL-38180 and DK-56260 and Digestive Disease Research Core Center Grant DK-52574 (particularly the Morphology Core). 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.

^¶ To whom correspondence should be addressed. Fax: 314-362-2033; E-mail: nod{at}im.wustl.edu.

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