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J. Biol. Chem., Vol. 279, Issue 38, 39199-39206, September 17, 2004

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STAT2 Nuclear Trafficking^*

Gregg Banninger and Nancy C. Reich¶

From the Graduate Program in Genetics, the Department of Pathology, Stony Brook University, Stony Brook, New York 11794-8691

STAT2 is a transcription factor critical to the signal transduction pathway of type I interferons (e.g. IFN). STAT2 resides primarily in the cytoplasm and is tyrosine-phosphorylated after IFN binds to cell surface receptors. In response to tyrosine phosphorylation STAT2 rapidly localizes to the nucleus and acquires the ability to bind specific DNA targets in association with two other proteins, STAT1 and IFN regulatory factor-9 (IRF-9). To elucidate the mechanisms that regulate cellular localization of STAT2, we investigated STAT2 nuclear trafficking both prior to tyrosine phosphorylation and after phosphorylation. Prior to phosphorylation, STAT2 is primarily resident in the cytoplasm, however, we found that it dynamically shuttles between nuclear and cytoplasmic compartments. The nuclear translocation of latent unphosphorylated STAT2 was found to be dependent on its constitutive association with IRF-9, and the export of STAT2 from the nucleus was contingent upon the function of an intrinsic nuclear export signal within the carboxyl terminus of STAT2. STAT2 export could be inhibited with leptomycin B, indicating a nuclear export signal within STAT2 is recognized by the CRM1 exportin carrier. In contrast, following tyrosine phosphorylation, STAT2 dimerizes with phosphorylated STAT1 and accumulates in the nucleus. In the absence of STAT1, STAT2 does not accumulate in the nucleus. In addition, subsequent to nuclear import of phosphorylated STAT2, it redistributes to the cytoplasm within an hour coordinate with its dephosphorylation in the nucleus. The regulation of STAT2 nuclear trafficking is distinct from the previously characterized STAT1 factor.

Received for publication, January 25, 2004 , and in revised form, May 28, 2004.

^* This work was supported by National Institutes of Health Grants RO1CA50773 and PPGCA28146 (to N. C. R.). 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: Tel.: 631-444-7503; Fax: 631-444-3424; nreich{at}notes.cc.sunysb.edu.

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