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Published 21 June 2004. doi:10.1083/jcb.200403057
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 6, 823-833
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Article

 Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1

Andreas Marg, Ying Shan, Thomas Meyer, Torsten Meissner, Martin Brandenburg, and Uwe Vinkemeier

Abteilung Zelluläre Signalverarbeitung, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, 13125 Berlin, Germany

Address correspondence to Uwe Vinkemeier, Abteilung Zelluläre Signalverarbeitung, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Tel.: 49-30-94793-171. Fax: 49-30-94793-179. email: vinkemeier{at}fmp-berlin.de

Interferon stimulation of cells leads to the tyrosine phosphorylation of latent Stat1 and subsequent transient accumulation in the nucleus that requires canonical transport factors. However, the mechanisms that control the predominantly cytoplasmic localization in unstimulated cells have not been resolved. We uncovered that constitutive energy- and transport factor-independent nucleocytoplasmic shuttling is a property of unphosphorylated Stat1, Stat3, and Stat5. The NH2- and COOH-terminal Stat domains are generally dispensable, whereas alkylation of a single cysteine residue blocked cytokine-independent nuclear translocation and thus implicated the linker domain into the cycling of Stat1. It is revealed that constitutive nucleocytoplasmic shuttling of Stat1 is mediated by direct interactions with the FG repeat regions of nucleoporin 153 and nucleoporin 214 of the nuclear pore. Concurrent active nuclear export by CRM1 created a nucleocytoplasmic Stat1 concentration gradient that is significantly reduced by the blocking of energy-requiring translocation mechanisms or the specific inactivation of CRM1. Thus, we propose that two independent translocation pathways cooperate to determine the steady-state distribution of Stat1.

Key Words: Stat1; transcription factor; nuclear transport; nucleoporins; interferon

The online version of this article contains supplemental material.

Abbreviations used in this paper: CIM, complete IM; EDM, energy depletion medium; IM, import mix; LMB, leptomycin B; MBP, maltose-binding protein; NEM, N-ethylmaleimide; NES, nuclear export signal; NPC, nuclear pore complex; Nup, nucleoporin; Stat, signal transducer and activator of transcription; TB, transport buffer.


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