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J. Biol. Chem., Vol. 279, Issue 49, 51022-51032, December 3, 2004

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Cytoplasmic Inositol Hexakisphosphate Production Is Sufficient for Mediating the Gle1-mRNA Export Pathway^*

Aimee L. Miller, Mythili Suntharalingam¶, Sylvia L. Johnson||, Anjon Audhya**, Scott D. Emr**, and Susan R. Wente¶¶

From the Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8240 and the ^**Department of Cellular and Molecular Medicine and the Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, California 92093-0668

Production of inositol hexakisphosphate (IP₆) by Ipk1, the inositol-1,3,4,5,6-pentakisphosphate 2-kinase, is required for Gle1-mediated mRNA export in Saccharomyces cerevisiae cells. To examine the network of interactions that require IP₆ production, an analysis of fitness defects was conducted in mutants harboring both an ipk1 null allele and a mutant allele in genes encoding nucleoporins or transport factors. Enhanced lethality was observed with a specific subset of mutants, including nup42, nup116, nup159, dbp5, and gle2, all of which had been previously connected to Gle1 function. Complementation of the nup116ipk1 and nup42ipk1 double mutants did not require the Phe-Gly repeat domains in the respective nucleoporins, suggesting that IP₆ was acting subsequent to heterogeneous nuclear ribonucleoprotein targeting to the nuclear pore complex. With Nup42 and Nup159 localized exclusively to the nuclear pore complex cytoplasmic side, we speculated that IP₆ may regulate a cytoplasmic step in mRNA export. To test this prediction, the spatial requirements for the production of IP₆ were investigated. Restriction of Ipk1 to the cytoplasm did not block IP₆ production. Moreover, coincident sequestering of both Ipk1 and Mss4 (an enzyme required for phosphatidylinositol 4,5-bisphosphate production) to the cytoplasm also did not block IP₆ production. Given that the kinase required for inositol 1,3,4,5,6-pentakisphosphate production (Ipk2) is localized in the nucleus, these results indicated that soluble inositides were diffusing between the nucleus and the cytoplasm. Additionally, the cytoplasmic production of IP₆ by plasma membrane-anchored Ipk1 rescued a gle1-2 ipk1-4 synthetic lethal mutant. Thus, cytoplasmic IP₆ production is sufficient for mediating the Gle1-mRNA export pathway.

Received for publication, August 16, 2004 , and in revised form, September 24, 2004.

^* This work was supported in part by a Kirsch Investigator award from the Steven and Michelle Kirsch Foundation (to S. R. W.) and Grant GM51219 from the National Institutes of Health (to S. R. W.). 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.

Present address: Dept. of Chemistry, Millersville University, Millersville, PA 17551.

^¶ Present address: Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110.

^|| Present address: Dept. of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110.

Present address: Ludwig Inst. for Cancer Research, La Jolla, CA 92093-0660.

Investigator of the Howard Hughes Medical Institute.

^¶¶ To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, Vanderbilt University Medical Center, 3120 MRBIII, 465 21st Ave. S., Nashville, TN 37232-8240. Tel.: 615-936-3443; Fax: 615-936-3439; E-mail: susan.wente{at}vanderbilt.edu.

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