STAT2 Nuclear Trafficking

STAT2 is a transcription factor critical to the signal transduction pathway of type I interferons (e.g. IFNα). STAT2 resides primarily in the cytoplasm and is tyrosine-phosphorylated after IFNα 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. STAT2 is a transcription factor critical to the signal transduction pathway of type I interferons (e.g. IFNα). STAT2 resides primarily in the cytoplasm and is tyrosine-phosphorylated after IFNα 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. The signal transducers and activators of transcription (STATs) 1The abbreviations used are: STAT, signal transducer and activator of transcription; SH2, Src homology 2; JAK, Janus kinase; IFN, type I interferon; TRF-9, IFN regulatory factor-9; ISGF3, IFN-stimulated gene factor 3; NLS, nuclear localization signal; NES, nuclear export signal; CRM1, chromosome region maintenance 1; GFP, green fluorescent protein; TRITC, tetramethylrhodamine isothiocyanate; GST, glutathione S-transferase. remain the only characterized DNA binding factors that are regulated directly by tyrosine phosphorylation (1Fu X.Y. Cell. 1992; 70: 323-335Abstract Full Text PDF PubMed Scopus (304) Google Scholar, 2Shuai K. Stark G.R. Kerr I.M. Darnell Jr., J.E. Science. 1993; 261: 1744-1746Crossref PubMed Scopus (690) Google Scholar, 3Gutch M.J. Daly C. Reich N.C. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11411-11415Crossref PubMed Scopus (64) Google Scholar, 4Schindler C. Shuai K. Prezioso V.R. Darnell Jr., J.E. Science. 1992; 257: 809-813Crossref PubMed Scopus (727) Google Scholar). Tyrosine phosphorylation confers new properties to the STAT factors by inducing dimerization via reciprocal phosphotyrosine and Src homology 2 (SH2) domain interactions. This conformational change can contribute to nuclear translocation and is essential for binding to specific DNA targets. The STAT1 and STAT2 factors are tyrosine-phosphorylated in the cytoplasm by Janus kinases (JAKs) activated in response to type I interferon (IFN) (5Velazquez L. Fellous M. Stark G.R. Pellegrini S. Cell. 1992; 70: 313-322Abstract Full Text PDF PubMed Scopus (714) Google Scholar, 6, Deleted in proofGoogle Scholar, 38Muller M. Laxton C. Briscoe J. Schindler C. Improta T. Darnell Jr., J.E. Stark G.R. Kerr I.M. EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (373) Google Scholar). The phosphorylated STATs subsequently dimerize and localize to the nucleus. The STAT2 factor is unique among the STATs in that it is associated constitutively with a distinct transcription factor, interferon regulatory factor-9 (IRF-9) (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 8Veals S.A. Schindler C. Leonard D. Fu X.Y. Aebersold R. Darnell Jr., J.E. Levy D.E. Mol. Cell. Biol. 1992; 12: 3315-3324Crossref PubMed Scopus (349) Google Scholar, 9Lau J.F. Parisien J.P. Horvath C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7278-7283Crossref PubMed Scopus (79) Google Scholar). After phosphorylation, a trimeric complex forms of STAT1·STAT2·IRF-9, known as IFN-stimulated gene factor 3 (ISGF3), that binds to a specific IFN-stimulated response element in the promoters of responsive genes (reviewed in Refs. 10Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Crossref PubMed Scopus (5062) Google Scholar, 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3388) Google Scholar, 12Levy D.E. Darnell Jr., J.E. Nat Rev Mol. Cell. Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar). A successful innate immune response to viral infection requires the induced expression of genes by ISGF3. Targeted gene disruptions of STAT1, STAT2, or IRF-9 clearly demonstrate that animals lacking one of these factors succumb to infection (13Durbin J.E. Hackenmiller R. Simon M.C. Levy D.E. Cell. 1996; 84: 443-450Abstract Full Text Full Text PDF PubMed Scopus (1304) Google Scholar, 14Meraz M.A. White J.M. Sheehan K.C. Bach E.A. Rodig S.J. Dighe A.S. Kaplan D.H. Riley J.K. Greenlund A.C. Campbell D. Carver-Moore K. DuBois R.N. Clark R. Aguet M. Schreiber R.D. Cell. 1996; 84: 431-442Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar, 15Park C. Li S. Cha E. Schindler C. Immunity. 2000; 13: 795-804Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). STATs serve as a link between the cell surface and the nucleus, and this requires their physical movement from the cytoplasm to the nucleus. Such movement between the cytoplasm and the nucleus is a tightly regulated process that requires specific protein signal sequences and soluble shuttling carriers that recognize these sequences and mediate transport through nuclear pore complexes (16Rout M.P. Aitchison J.D. J. Biol. Chem. 2001; 276: 16593-16596Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 17Mattaj I.W. Englmeier L. Annu. Rev. Biochem. 1998; 67: 265-306Crossref PubMed Scopus (1011) Google Scholar, 18Gorlich D. Kutay U. Annu. Rev. Cell Dev. Biol. 1999; 15: 607-660Crossref PubMed Scopus (1676) Google Scholar, 19Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Crossref PubMed Scopus (427) Google Scholar, 20Macara I.G. Microbiol. Mol. Biol. Rev. 2001; 65: 570-594Crossref PubMed Scopus (746) Google Scholar). Nuclear import of proteins larger than 50 kDa requires the expression of a nuclear localization signal (NLS). The best characterized NLSs contain stretches of basic residues and are recognized by the mammalian importin-α adapter family. The importin-α proteins bind importin-β1, which mediates movement through the nuclear pore complex. The exit of proteins from the nucleus shares many properties with the import process. Export requires the presence of a nuclear export signal (NES) on proteins destined for the cytoplasm and requires recognition of the NES by soluble carriers called exportins. One of the exportins, chromosome region maintenance 1 (CRM1), recognizes a common NES composed of a short hydrophobic sequence rich in leucine residues. Some proteins possess both NLS and NES sequences, and cellular localization is determined by the relative function of the NLS and NES. The function of these signals may be or it may be regulated by by or by in the cytoplasm or nucleus. In a protein may not possess an intrinsic NLS or NES, association with protein to contribute these cellular localization STAT1 and STAT2 not to possess NLSs that function however, dimerization via a conformational change that to a of NLS function T. K. T. EMBO J. 1997; PubMed Scopus Google Scholar, C. Reich N.C. EMBO J. 2000; PubMed Google Scholar, G. C. Reich N.C. EMBO J. 2002; PubMed Scopus Google Scholar, K. R. J. M. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. K. L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). STAT1 and are rapidly to the nucleus and to with one specific importin-α The DNA binding domain of STAT1 is critical for NLS function of the and recognition of Nuclear export is in the cellular localization of proteins the to nuclear can the NES and nuclear The DNA binding domain of STAT1 a NES that can function and to be STAT1 are to in the nucleus STAT1 from DNA and the NES to CRM1 in the of STAT1 to the The DNA binding domain of STAT1 to with nuclear import and export signals to it is in the the an of its function as a signal transducer and activator of STAT2 is distinct among the STATs in its ability to bind to IRF-9 and this that STAT2 localization may be regulated from STAT1 (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). IRF-9, known as or IFN-stimulated gene factor 3 is a of the of transcription factors that in and cellular response to viral S.A. Schindler C. Leonard D. Fu X.Y. Aebersold R. Darnell Jr., J.E. Levy D.E. Mol. Cell. Biol. 1992; 12: 3315-3324Crossref PubMed Scopus (349) Google Scholar, T. K. A. Annu. Rev. 2001; PubMed Scopus Google Scholar, J. Rev. 1997; PubMed Scopus Google Scholar, N.C. J. 2002; PubMed Scopus Google Scholar). contain nuclear localization signals that their translocation to the nucleus, however, in a latent in the cytoplasm of the cell and only to the nucleus following an The of the of the is the of their DNA binding carboxyl are known to with distinct transcription and this to their unique on gene The carboxyl region of IRF-9 with the region of STAT2, and the ability of IRF-9 to bind DNA to specific recognition of the ISGF3. In this we that the unphosphorylated STAT2 constitutively shuttles in and of the nucleus. STAT2 is the nucleus via association with IRF-9, a NES in the carboxyl terminus of STAT2 in localization of the complex to the tyrosine phosphorylation in response to IFN STAT2 dimerizes with STAT1, and this conformational change in a of NLS to with the STAT1 STAT2 to mechanisms that regulate its nuclear trafficking both prior to and subsequent to tyrosine phosphorylation. Cell and cell of G. R. and in with with from and leptomycin from DNA with and previously (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). STAT2 and gene by with and prior to of green fluorescent protein gene the of was the and by DNA was used for and phosphotyrosine was used in was used for and or used as for was used as for by binding to protein on and with proteins or proteins in following a for with a and with a 2 and in are of from two to and to the of or in a of as in the in 50 with by and to by with phosphotyrosine or by and the importin-α previously C. Reich N.C. Mol. Cell. Biol. 2000; PubMed Scopus Google or of E. and M. of M. C. M. S. D. E. Mol. Cell. Biol. 1999; PubMed Google Scholar). The in in the presence of proteins with or to glutathione The binding 1 1 and the complexes to glutathione and proteins and by and STAT2 between and in the of IFN the cellular localization of STAT2 prior to and subsequent to IFN protein was by The clearly a cytoplasmic localization of latent unphosphorylated STAT2 in the absence of IFN To unphosphorylated STAT2 is to the cytoplasm or it to the nucleus is to the cytoplasm, we the of leptomycin B, an of the CRM1 exportin carrier. of with leptomycin in the absence of IFN was found to the nuclear of STAT2 This that STAT2 shuttles between the nucleus and the cytoplasm, nuclear export by CRM1 latent STAT2 in the cytoplasm STAT2 to with the factor IRF-9 both prior to IFN and following IFN (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 9Lau J.F. Parisien J.P. Horvath C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7278-7283Crossref PubMed Scopus (79) Google Scholar). previously the domain of STAT2 to be to with IRF-9 (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The terminus of IRF-9 a DNA binding domain and a NLS that mediates its nuclear localization of IRF-9 that a nuclear however, of STAT2 to of IRF-9 to the cytoplasm J.F. Parisien J.P. Horvath C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7278-7283Crossref PubMed Scopus (79) Google Scholar). This to association of STAT2 with IRF-9 is for nuclear translocation of unphosphorylated STAT2, or a constitutive nuclear localization signal is intrinsic to STAT2. To this we localization of STAT2 in that IRF-9 S. J. M. Kerr I.M. Stark G.R. Mol. Cell. Biol. PubMed Scopus Google Scholar). of STAT2 in that STAT2 in the cytoplasm of these of leptomycin and The of STAT2 to accumulate in the nucleus of after with leptomycin that IRF-9 was for STAT2 nuclear import in the absence of STAT2 in the nucleus following leptomycin in the presence of IRF-9, the nuclear was not This that the of IRF-9 To this we IRF-9 in by and localization of STAT2. of STAT2 that STAT2 primarily in the cytoplasm of IRF-9 of IRF-9 in these a nuclear presence of IRF-9, STAT2 was and IRF-9 in the nucleus of these to a localization of STAT2 to the nucleus, only in IRF-9 and that complexes between the nucleus and the cytoplasm in and STAT2 a NES that localizes the complexes to the IRF-9 with NLS within the terminus of IRF-9 that to be for IRF-9 nuclear localization J.F. Parisien J.P. Horvath C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7278-7283Crossref PubMed Scopus (79) Google Scholar). are characterized mammalian importin-α that importin-α carriers are is for and of mammalian M. C. M. S. D. E. Mol. Cell. Biol. 1999; PubMed Google Scholar, D. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Mol. Cell. Biol. 1998; PubMed Google Scholar, T. T. T. S. T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). To IRF-9 is recognized by specific of the importin-α we in importin-α binding importin-α in in the presence of and with glutathione or to glutathione The proteins from the and by and IRF-9 was found to bind to a specific of importin-α was with and and with This is in distinct to the binding of STAT1 tyrosine-phosphorylated to T. K. T. EMBO J. 1997; PubMed Scopus Google Scholar). STAT2 a NES within the region of STAT2 for its nuclear we STAT2 and to and the cellular localization of proteins in the presence of of the are in STAT2 that the domain be to with IRF-9 and be the nucleus by the constitutive NLS in IRF-9 (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). A NES in STAT2 the complexes to the cytoplasm, however, the of leptomycin STAT2 nuclear presence by of a NES in STAT2 maintenance of binding to IRF-9 in of STAT2 in the nucleus in the absence or presence of leptomycin The with IRF-9 to the of STAT2 STAT2 and STAT2 to the cytoplasm, in the presence of leptomycin in the nucleus, with the presence of a NES. The STAT2 the domain that is for binding to IRF-9, as it not to the nucleus, the IRF-9 for nuclear import of STAT2. The STAT2 STAT2 and STAT2 in the nucleus in the absence of leptomycin B, indicating that these proteins the NES The STAT2 as STAT2 and in the cytoplasm with leptomycin B, indicating the presence of the NES. and expression of by not a region between and that a sequence critical for STAT2 nuclear The of STAT2 as an NES to that the STAT2 carboxyl terminus a NES, we this region could nuclear of a The of and its of an intrinsic NLS or NES the protein to between the nuclear and cytoplasmic of an sequence to to its from the nucleus by nuclear The of STAT2 to and in to its localization by The STAT2 was from the nucleus, indicating the presence of a NES A region of STAT2 to was not from the nucleus A region of the DNA binding domain of STAT2 that shares homology to the NES region of STAT1 cytoplasmic of only in of the The NES of unphosphorylated STAT2 to the domain region of STAT2 between This region stretches of leucine residues that could contribute to nuclear export To the of leucine residues in this was on the STAT2 residues to and with and the for their on nuclear export The on export and the nuclear export that a NES in the carboxyl terminus of STAT2 in region STAT2 STAT1 IRF-9 for Nuclear following response to STAT1 and STAT2 tyrosine-phosphorylated and via interactions. The known as interferon (ISGF3), forms in the cytoplasm prior to nuclear translocation Kerr I.M. Stark G.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D.E. R. Darnell Jr., J.E. Dev. 3: PubMed Scopus Google Scholar). Nuclear transport of the tyrosine-phosphorylated complex to from a conformational change of the proteins and recognition by the T. K. T. EMBO J. 1997; PubMed Scopus Google Scholar, G. C. Reich N.C. EMBO J. 2002; PubMed Scopus Google Scholar, R. K. L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). IRF-9 is known to be essential for the ability of to bind the response element DNA its in the nuclear import of to be To IRF-9 binding to STAT2 was for nuclear localization in response to we localization of STAT2 by in the presence or absence of In the absence of IFN unphosphorylated STAT2 primarily in the cytoplasm of and a cell that IRF-9 S. J. M. Kerr I.M. Stark G.R. Mol. Cell. Biol. PubMed Scopus Google In response to tyrosine-phosphorylated STAT2 in the nucleus of both and that IRF-9 is not for nuclear import of STAT2. the localization of tyrosine-phosphorylated STAT2 in a cell lacking STAT1 M. Laxton C. Briscoe J. Schindler C. Improta T. Darnell Jr., J.E. Stark G.R. Kerr I.M. EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (373) Google Scholar). In to or STAT2 not accumulate in the nucleus of after STAT2 was tyrosine-phosphorylated T. Schindler C. Horvath C.M. Kerr I.M. Stark G.R. Darnell Jr., J.E. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google and not the of a of is for nuclear of tyrosine-phosphorylated STAT2. The specific that was previously to bind the is distinct from the importin-α that recognize IRF-9 G. C. Reich N.C. EMBO J. 2002; PubMed Scopus Google Scholar). STAT2 Nuclear in to the of STAT2 nuclear we used of STAT2 to its localization with after with for a the was from the and STAT2 localization was subsequent to from to STAT2 in the nucleus of after a by after of STAT2 to in the cytoplasm and after the of STAT2 to the The of STAT2 in the cytoplasm an nuclear export of the To export of STAT2 was by CRM1, the was in the presence of the specific CRM1 leptomycin inhibited the of STAT2 to the cytoplasm following The was after that CRM1 a in the nuclear export of STAT2 following by the signal To STAT2 nuclear export following IFN with the of STAT2 tyrosine phosphorylation, we the phosphorylation of STAT2 after in the absence or presence of leptomycin A IFN as in was cell and STAT2 was by with specific STAT2 phosphotyrosine of IFN to a in STAT2 tyrosine phosphorylation, however, this phosphorylation following the of of the STAT2 phosphotyrosine signal to the STAT2 signal a of after by and than by The of dephosphorylation with the of STAT2 from the nucleus to the STAT2 nuclear export with leptomycin not the of dephosphorylation indicating that dephosphorylation of STAT2 can in the nucleus. of STAT2 in its from STAT1 and from DNA The change in and of STAT2 from DNA may with CRM1 recognition of the STAT2 export STAT2 Nuclear Export following IFN NES of STAT2 clearly an in nuclear export of unphosphorylated complexes prior to To this NES to the export of STAT2 following tyrosine phosphorylation and dimerization with STAT1, we the cellular localization of STAT2 with specific NES following with type or a NES and with for The cellular localization of STAT2 was by following In to type STAT2, which was by following IFN the NES nuclear of indicating export and by of the NES protein in the in phosphorylation between the type and the NES as by a to tyrosine-phosphorylated STAT2 following not that is a NES in the carboxyl and one or in STAT2 or an associated that serve to export STAT2 from the nucleus subsequent to its cellular localization is critical to the function of transcription this we investigated the localization of STAT2, a transcription factor essential for the innate immune response to type I IFN was used to the localization of unphosphorylated STAT2 in to tyrosine-phosphorylated STAT2. STAT2 resides in the cytoplasm of the of an of nuclear leptomycin B, clearly its presence in the nucleus. This that unphosphorylated STAT2 is not dynamically shuttles between the nucleus and STAT2 is distinct among the STAT in that it binds to a factor, IRF-9 (7Martinez-Moczygemba M. Gutch M.J. French D.L. Reich N.C. J. Biol. Chem. 1997; 272: 20070-20076Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). IRF-9 a constitutive NLS, we the that the complex is the nucleus by IRF-9 J.F. Parisien J.P. Horvath C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7278-7283Crossref PubMed Scopus (79) Google Scholar). of that IRF-9 and of STAT2 that not bind IRF-9 the nuclear import of unphosphorylated STAT2 was by IRF-9 Nuclear of STAT2 in the absence of IFN on the of its domain with IRF-9, and IRF-9 was to directly with and of STAT2 to a NES that mediate export of from the nucleus in the absence of IFN of STAT2, we a distinct NES in its carboxyl The carboxyl NES a in nuclear export of the unphosphorylated STAT2. The shuttling of the complexes may contribute to a in response to IFN the NES of STAT2 may contribute to signal by IRF-9 to the cytoplasm to an DNA binding factor from the nucleus. of IRF-9 was found by and to gene expression of genes J.F. Parisien J.P. Horvath C.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and not export of IRF-9 by STAT2 serve as one to this STAT2 a domain within its carboxyl terminus and IRF-9 an DNA binding the of this complex in the nucleus may S.A. Schindler C. Leonard D. Fu X.Y. Aebersold R. Darnell Jr., J.E. Levy D.E. Mol. Cell. Biol. 1992; 12: 3315-3324Crossref PubMed Scopus (349) Google Scholar, M. S. L. S. Levy D.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The constitutive NES in STAT2 that STAT2 IRF-9 and complexes to the cytoplasm prior to and following tyrosine dephosphorylation of in the nucleus. In response to type I both STAT1 and STAT2 are tyrosine-phosphorylated in the cytoplasm by kinases The phosphorylated STAT1 and STAT2 proteins via reciprocal and the of this to a conformational change and the of a NLS G. C. Reich N.C. EMBO J. 2002; PubMed Scopus Google Scholar). The NLS in the is recognized by a specific that nuclear translocation of the complex and in the nucleus for after IFN This nuclear the of STAT2 in the nucleus it a constitutive NES in its carboxyl are mechanisms that may contribute to of phosphorylated STAT2 in the nucleus. The ability of the tyrosine-phosphorylated complex to bind DNA may it in the nucleus and export by dimerization with STAT1 may a conformational change that the NES of STAT2 recognition by in the nucleus STAT2 from STAT1 and DNA and its NES. with the STAT1 an NES within its DNA binding domain that is STAT1 are to DNA to CRM1 from is that the binding of as to STAT2 in the complex may the carboxyl NES. to bind to the domain of STAT2 S. R. S. E. A. D. 1996; PubMed Scopus Google Scholar). One or of these mechanisms may contribute to the nuclear of tyrosine-phosphorylated STAT2. The ability to the CRM1 export with leptomycin to the that transcription factors previously to be cytoplasmic between nuclear and cytoplasmic compartments. the latent transcription factor shuttles in and of the nucleus, nuclear export is it accumulates in the cytoplasm C. Reich N.C. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). viral infection is activated by phosphorylation and it accumulates in the nucleus by to is the transcription factor, which is in in the cytoplasm in an it shuttles between the cytoplasm and nucleus Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). it dimerizes with other and this binding its NES and to in the nucleus. is not shuttling is a to a is that factors as may in the nucleus and bind to S. K. Science. 1999; PubMed Scopus Google Scholar). complexes dynamically between the nucleus and cytoplasm, and the function of a constitutive NES in STAT2 may serve to a transcription factor from the nucleus and on gene the of the STAT transcription factor many are by their in response to and their with distinct transcription and their regulation of distinct gene we in this the regulation of STAT2 nuclear trafficking is distinct from that of unique of STAT contribute to their in specific the of the for their and for and and are for the of and