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Vol. 17, Issue 12, 5309-5323, December 2006

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The Unfolded Protein Response Transducer Ire1p Contains a Nuclear Localization Sequence Recognized by Multiple Importins

Laurence Goffin^*,,, Sadanand Vodala^*,, Christine Fraser^*, Joanne Ryan^*, Mark Timms^*, Sarina Meusburger^*, Bruno Catimel, Edouard C. Nice, Pamela A. Silver^||, Chong-Yun Xiao^¶, David A. Jans^¶,#, and Mary-Jane H. Gething^*

*Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia; Ludwig Institute for Cancer Research, Parkville, Victoria 3052, Australia; ^||Department of Systems Biology, Harvard Medical School, Boston, MA 02115; ^#Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Canberra, ACT 2601, Australia; and ^¶Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia

Submitted April 11, 2006; Revised August 31, 2006; Accepted September 29, 2006
Monitoring Editor: Reid Gilmore

The Ire1p transmembrane receptor kinase/endonuclease transduces the unfolded protein response (UPR) from the endoplasmic reticulum (ER) to the nucleus in Saccharomyces cerevisiae. In this study, we analyzed the capacity of a highly basic sequence in the linker region of Ire1p to function as a nuclear localization sequence (NLS) both in vivo and in vitro. This 18-residue sequence is capable of targeting green fluorescent protein to the nucleus of yeast cells in a process requiring proteins involved in the Ran GTPase cycle that facilitates nuclear import. Mutagenic analysis and importin binding studies demonstrate that the Ire1p linker region contains overlapping potential NLSs: at least one classical NLS (within sequences ₆₄₂KKKRKR₆₄₇ and/or ₆₅₃KKGR₆₅₆) that is recognized by yeast importin (Kap60p) and a novel NLS (₆₄₆KRGSRGGKKGRK₆₅₇) that is recognized by several yeast importin homologues. Kinetic binding data suggest that binding to importin proteins would predominate in vivo. The UPR, and in particular ER stress-induced HAC1 mRNA splicing, is inhibited by point mutations in the Ire1p NLS that inhibit nuclear localization and also requires functional RanGAP and Ran GEF proteins. The NLS-dependent nuclear localization of Ire1p would thus seem to be central to its role in UPR signaling.

These authors contributed equally to this work.

Present address: Department of Tumor Immunology, Ludwig Institute for Cancer Research, Lausanne 1066, Switzerland.

Address correspondence to: Mary-Jane H. Gething (m.gething{at}unimelb.edu.au)

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