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MBC in Press, published online ahead of print October 11, 2006
Mol. Biol. Cell 10.1091/mbc.E06-04-0292

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Submitted on April 11, 2006
Revised on August 31, 2006
Accepted on September 29, 2006

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

Laurence Goffin,*{dagger}{ddagger} Sadanand Vodala,*{dagger} Christine Fraser,* Joanne Ryan,* Mark Timms,* Sarina Meusburger,* Bruno Catimel,{sect} Edouard C. Nice,{sect} 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; {sect}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; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia

Monitoring Editor: Reid Gilmore

The Ire1p transmembrane receptor kinase/endonuclease transduces the unfolded protein response (UPR) from the ER to the nucleus in S. 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 19-residue sequence is capable of targeting GFP 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 cNLS (within sequences 642KKKRKR647 and/or 653KKGR656) that is recognized by yeast importin {alpha} (Kap60p), and a novel {beta}NLS (646KRGSRGGKKGRK657) that is recognized by several yeast importin {beta} homologues. Kinetic binding data suggest that binding to importin {beta} 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. Ire1p’s NLS-dependent nuclear localization would thus appear to be central to its role in UPR signaling.

{dagger}These authors contributed equally to this work.

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

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




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