Role of the Tetradecapeptide Repeat Domain of Human Histone Deacetylase 6 in Cytoplasmic Retention

Histone deacetylase 6 (HDAC6) contains tandem catalytic domains and a ubiquitin-binding zinc finger and displays deacetylase activity toward acetylated microtubules. Here we show that unlike its orthologs from Caenorhabditis elegans, Drosophila, and mouse, human HDAC6 possesses a tetradecapeptide repeat domain located between the second deacetylase domain and the C-terminal ubiquitin-binding motif. Related to this structural difference, the cytoplasmic localization of human, but not murine, HDAC6 is resistant to treatment with leptomycin B (LMB). Although it is dispensable for the deacetylase and ubiquitin binding activities of human HDAC6, the tetradecapeptide repeat domain displays acetyl-microtubule targeting ability. Moreover, it forms a unique structure and is required for the LMB-resistant cytoplasmic localization of human HDAC6. Besides the tetradecapeptide repeat domain, human HDAC6 possesses two LMB-sensitive nuclear export signals and a nuclear localization signal. These results thus indicate that the cytoplasmic localization for murine and human HDAC6 proteins is differentially regulated and suggest that the tetradecapeptide repeat domain serves as an important sequence element to stably retain human HDAC6 in the cytoplasm. Histone deacetylase 6 (HDAC6) contains tandem catalytic domains and a ubiquitin-binding zinc finger and displays deacetylase activity toward acetylated microtubules. Here we show that unlike its orthologs from Caenorhabditis elegans, Drosophila, and mouse, human HDAC6 possesses a tetradecapeptide repeat domain located between the second deacetylase domain and the C-terminal ubiquitin-binding motif. Related to this structural difference, the cytoplasmic localization of human, but not murine, HDAC6 is resistant to treatment with leptomycin B (LMB). Although it is dispensable for the deacetylase and ubiquitin binding activities of human HDAC6, the tetradecapeptide repeat domain displays acetyl-microtubule targeting ability. Moreover, it forms a unique structure and is required for the LMB-resistant cytoplasmic localization of human HDAC6. Besides the tetradecapeptide repeat domain, human HDAC6 possesses two LMB-sensitive nuclear export signals and a nuclear localization signal. These results thus indicate that the cytoplasmic localization for murine and human HDAC6 proteins is differentially regulated and suggest that the tetradecapeptide repeat domain serves as an important sequence element to stably retain human HDAC6 in the cytoplasm. Lysine acetylation has been shown to regulate functions of histones, about 40 transcription factors, and over 30 other proteins (1Yang X.J. BioEssays. 2004; 26: 1076-1087Crossref PubMed Scopus (308) Google Scholar). This modification process is reversible and maintained by opposing actions of lysine acetyltransferases and deacetylases in vivo. Among the latter are histone deacetylases (HDACs). 1The abbreviations used are: HDAC, histone deacetylase; hHDAC6, human HDAC6; mHDAC6, murine HDAC6; dHDAC6, Drosophila HDAC6; SE14, serine-glutamate containing tetradecapeptide; LMB, leptomycin B; HUB, HDAC6-, USP3- and BRAP2-related zinc finger; CRM1, chromosome regulation and maintenance 1; NES, nuclear export signal; NLS, nuclear localization signal; CRS, cytoplasmic retention signal; ActD, actinomycin D; GFP, green fluorescent protein; PMSF, phenylmethylsulfonyl fluoride; RT, reverse transcription; PBS, phosphate-buffered saline; TSA, trichostatin A.1The abbreviations used are: HDAC, histone deacetylase; hHDAC6, human HDAC6; mHDAC6, murine HDAC6; dHDAC6, Drosophila HDAC6; SE14, serine-glutamate containing tetradecapeptide; LMB, leptomycin B; HUB, HDAC6-, USP3- and BRAP2-related zinc finger; CRM1, chromosome regulation and maintenance 1; NES, nuclear export signal; NLS, nuclear localization signal; CRS, cytoplasmic retention signal; ActD, actinomycin D; GFP, green fluorescent protein; PMSF, phenylmethylsulfonyl fluoride; RT, reverse transcription; PBS, phosphate-buffered saline; TSA, trichostatin A. According to sequence homology to yeast prototypes, known mammalian HDACs have been grouped into three classes (2Cress W.D. Seto E. J. Cell. Physiol. 2000; 184: 1-16Crossref PubMed Scopus (575) Google Scholar, 3Khochbin S. Verdel A. Lemercier C. Seigneurin-Berny D. Curr. Opin. Genet. Dev. 2001; 11: 162-166Crossref PubMed Scopus (327) Google Scholar, 4Grozinger C.M. Schreiber S.L. Chem. Biol. 2002; 9: 3-16Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar, 5Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar). Within class II, there are HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. The catalytic domains of these deacetylases display significant sequence similarity to that of yeast Hda1 (6Rundlett S.E. Carmen A.A. Kobayashi R. Bavykin S. Turner B.M. Grunstein M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14503-14508Crossref PubMed Scopus (517) Google Scholar). Among class II members, HDAC4, HDAC5, HDAC7, and HDAC9 constitute a subclass (IIa), whereas HDAC6 and HDAC10 form class IIb. It is well established now that class IIa members are enzymatic transcriptional corepressors whose functions are regulated by nucleocytoplasmic trafficking (5Verdin E. Dequiedt F. Kasler H.G. Trends Genet. 2003; 19: 286-293Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 7McKinsey T.A. Zhang C.L. Olson E.N. Trends Biochem. Sci. 2002; 27: 40-47Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar). HDAC6, a class IIb member, possesses tandem catalytic domains and a Cys/His-rich motif (8Verdel A. Khochbin S. J. Biol. Chem. 1999; 274: 2440-2445Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 9Grozinger C.M. Hassig C.A. Schreiber S.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 4868-4873Crossref PubMed Scopus (648) Google Scholar). The Cys/His-rich motif shows significant sequence homology to the BRCA1-associated protein BRAP2 and several ubiquitin-specific proteases, and is known as a DAUP (deacetylase-ubiquitin-specific protease) domain (10Amerik A.Y. Li S.J. Hochstrasser M. Biol. Chem. 2000; 381: 981-992Crossref PubMed Scopus (158) Google Scholar), HUB (HDAC6-, USP3- and BRAP2-related) finger (11Bertos N.R. Wang A.H. Yang X.J. Biochem. Cell Biol. 2001; 79: 243-252Crossref PubMed Scopus (238) Google Scholar), ZnF-UBP (ubiquitin C-terminal hydrolase-like zinc finger) (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar), PAZ (polyubiquitin-associated zinc finger) (13Hook S.S. Orian A. Cowley S.M. Eisenman R.N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13425-13430Crossref PubMed Scopus (170) Google Scholar), and BUZ (bound to ubiquitin zinc finger) (14Kawaguchi Y. Kovacs J.J. McLaurin A. Vance J.M. Ito A. Yao T.P. Cell. 2003; 115: 727-738Abstract Full Text Full Text PDF PubMed Scopus (1184) Google Scholar). It specifically interacts with ubiquitin (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar, 13Hook S.S. Orian A. Cowley S.M. Eisenman R.N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13425-13430Crossref PubMed Scopus (170) Google Scholar) and may function as a monoubiquitin ligase (15Kovacs J.J. Hubbert C. Yao T.P. Novartis Found Symp. 2004; 259: 170-177PubMed Google Scholar). Related to this, HDAC6 binds to phospholipase A2-activating protein and p97, both of which have been implicated in regulating ubiquitin-dependent degradation (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar). In addition, HDAC6 colocalizes with microtubules and deacetylates α-tubulin to regulate cell motility (16Hubbert C. Guardiola A. Shao R. Kawaguchi Y. Ito A. Nixon A. Yoshida M. Wang X.F. Yao T.P. Nature. 2002; 417: 455-458Crossref PubMed Scopus (1759) Google Scholar, 17Palazzo A. Ackerman B. Gundersen G.G. Nature. 2002; 421: 230Crossref Scopus (203) Google Scholar, 18Matsuyama A. Shimazu T. Sumida Y. Saito A. Yoshimatsu Y. Seigneurin-Berny D. Osada H. Komatsu Y. Nishino N. Khochbin S. Horinouchi S. Yoshida M. EMBO J. 2002; 21: 6820-6831Crossref PubMed Scopus (570) Google Scholar, 19Zhang Y. Li N. Caron C. Matthias G. Hess D. Khochbin S. Matthias P. EMBO J. 2003; 22: 1168-1179Crossref PubMed Scopus (568) Google Scholar, 20Haggarty S.J. Koeller K.M. Wong J.C. Grozinger C.M. Schreiber S.L. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 4389-4394Crossref PubMed Scopus (893) Google Scholar, 21North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar), aggresome formation (14Kawaguchi Y. Kovacs J.J. McLaurin A. Vance J.M. Ito A. Yao T.P. Cell. 2003; 115: 727-738Abstract Full Text Full Text PDF PubMed Scopus (1184) Google Scholar), and immune synapse organization (22Serrador J.M. Cabrero J.R. Sancho D. Mittelbrunn M. Urzainqui A. Sanchez-Madrid F. Immunity. 2004; 20: 417-428Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). Therefore, HDAC6 plays important roles in the cytoplasm. Inhibition of CRM1-dependent nuclear export results in accumulation of murine HDAC6 (mHDAC6) in the nucleus (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), so its cytoplasmic localization may be regulated. Different from the Caenorhabditis elegans, Drosophila, and murine orthologs, human HDAC6 (hHDAC6) possesses eight consecutive Ser-Glu-containing tetradecapeptide (SE14) repeats between the second deacetylase domain and the C-terminal ubiquitin-binding zinc finger (11Bertos N.R. Wang A.H. Yang X.J. Biochem. Cell Biol. 2001; 79: 243-252Crossref PubMed Scopus (238) Google Scholar). Here we report that the cytoplasmic localization of hHDAC6 is resistant to treatment with leptomycin B (LMB), demonstrate that the SE14 repeat domain is responsible for this resistance, and show that hHDAC6 possesses intrinsic nuclear and export these results with its murine hHDAC6 possesses for its cytoplasmic for hHDAC6 and by from HDAC6 by with by with and by with from murine and to the by and used to to of with and of of used in a of 30 of in the by and for of from by and in with and The in with and nuclear as 11: PubMed Scopus Google Scholar). a 6 to a protein The with B and containing of the a by and of hHDAC6 in hHDAC6 sequence into with a C-terminal the and used to as a in with and and with phosphate-buffered in B containing and to by and activities by the of from as A.H. N.R. M. N. M. J. J. Yang X.J. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). in of and containing The to for and by the of of with of of the to as A. Shimazu T. Sumida Y. Saito A. Yoshimatsu Y. Seigneurin-Berny D. Osada H. Komatsu Y. Nishino N. Khochbin S. Horinouchi S. Yoshida M. EMBO J. 2002; 21: 6820-6831Crossref PubMed Scopus (570) Google Scholar). in containing with of hHDAC6 and in of PMSF, and trichostatin and for 30 to the of the for and and ubiquitin as (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar). C-terminal of hHDAC6 as a protein and as A.H. J. N.R. M. Yang X.J. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). The protein protein and into a for and A.H. J. N.R. M. Yang X.J. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar, N. N.R. N. Wang A.H. M. Yang Y. Yang X.J. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) used with with and in of and with the cell by and for in a The by and as the cytoplasmic The from the in of containing and for 30 the as nuclear and as A.H. Yang X.J. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). SE14 of hHDAC6 its tandem catalytic domains and the ubiquitin-binding zinc hHDAC6 possesses eight SE14 repeats with the sequence and are shown in and repeats with the sequence It is which the structure of this domain, but the of repeats that this domain may have a unique structure and a in regulating the function of this SE14 repeat domain is not in the of C. elegans, Drosophila, mouse, and HDAC6 proteins and (8Verdel A. Khochbin S. J. Biol. Chem. 1999; 274: 2440-2445Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, C.M. C.A. S. A. Turner B.M. Cell 2001; PubMed Scopus Google Scholar). that the HDAC6 sequence (8Verdel A. Khochbin S. J. Biol. Chem. 1999; 274: 2440-2445Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar) not an an SE14 repeat domain, from three murine and to with the SE14 repeat domain the HDAC6 sequence (8Verdel A. Khochbin S. J. Biol. Chem. 1999; 274: 2440-2445Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar), the to be there an with an SE14 repeat domain, the be shown in a of from three that this to the HDAC6 organization of the hHDAC6 and that there are hHDAC6 the SE14 repeat domain not Therefore, the SE14 repeat domain is in human, but not murine, HDAC6. of the SE14 in the of HDAC6 of the SE14 repeat domain that it may the structure of this, to the of cell a 6 and the by with hHDAC6 in to a of This is the of hHDAC6 the of hHDAC6 is to with other we hHDAC6 in from these the 6 and the by with to with hHDAC6, hHDAC6 from to a of the of hHDAC6 of hHDAC6, from that the protein is not that the of hHDAC6 is not to with other the of hHDAC6 is to we its ability. this, hHDAC6 with in These two proteins with and and shown in and not with that not In with this, Drosophila HDAC6 is C.M. C.A. S. A. Turner B.M. Cell 2001; PubMed Scopus Google Scholar). the SE14 repeat domain to the of hHDAC6, two C-terminal and the the HUB the latter possesses the HUB finger the SE14 repeat domain hHDAC6 and these two in as and to as shown in three HDAC6 from hHDAC6 the 6 as an as a hHDAC6, that the HUB domain not the of hHDAC6 the to that the SE14 repeat domain is responsible for the of hHDAC6 in These results indicate that the SE14 repeat domain may form an structure and the structure of of the SE14 for of hHDAC6 the SE14 repeat domain functions of this, hHDAC6 in and to shown in the hHDAC6 protein activity as that in and from the SE14 repeat domain the activity of hHDAC6, we the and shown in both to be as as the hHDAC6 that the SE14 repeat domain is not required for the activity of Besides its deacetylase activity toward histones, HDAC6 deacetylates α-tubulin (16Hubbert C. Guardiola A. Shao R. Kawaguchi Y. Ito A. Nixon A. Yoshida M. Wang X.F. Yao T.P. Nature. 2002; 417: 455-458Crossref PubMed Scopus (1759) Google Scholar, 18Matsuyama A. Shimazu T. Sumida Y. Saito A. Yoshimatsu Y. Seigneurin-Berny D. Osada H. Komatsu Y. Nishino N. Khochbin S. Horinouchi S. Yoshida M. EMBO J. 2002; 21: 6820-6831Crossref PubMed Scopus (570) Google Scholar, 19Zhang Y. Li N. Caron C. Matthias G. Hess D. Khochbin S. Matthias P. EMBO J. 2003; 22: 1168-1179Crossref PubMed Scopus (568) Google Scholar, 21North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar), so we the SE14 repeat domain the deacetylase activity of this, with for hHDAC6 and In this to the SE14 repeat with and by shown in the HDAC6 α-tubulin in vivo. with this, the and HDAC6 proteins both α-tubulin in that the SE14 repeat domain is dispensable for the deacetylase activity of of the SE14 in HUB finger of HDAC6 binds to ubiquitin (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar, 13Hook S.S. Orian A. Cowley S.M. Eisenman R.N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13425-13430Crossref PubMed Scopus (170) Google Scholar). of its to this finger the SE14 repeat domain may the ubiquitin binding activity of this, and human HDAC6 proteins in and for the to a we and its in which and for ubiquitin are with (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar). (12Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. Khochbin S. Mol. Cell. Biol. 2001; 21: 8035-8044Crossref PubMed Scopus (273) Google Scholar), mHDAC6, but not hHDAC6 and the to that the SE14 repeat domain not the ubiquitin binding of Moreover, the SE14 repeat domain not to ubiquitin not LMB-resistant of hHDAC6 is cytoplasmic (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), so we the localization of this, nuclear and cytoplasmic from and of these with a the C-terminal of hHDAC6 that hHDAC6 cytoplasmic not Moreover, to be cytoplasmic in and and Therefore, mHDAC6, hHDAC6 is a cytoplasmic is from the nucleus in a CRM1-dependent (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), so we hHDAC6 is regulated. this and with N. N. H. D. B. Yoshida M. Horinouchi S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). the cytoplasmic localization of by this treatment and (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), treatment the nuclear accumulation of and These results indicate that the cytoplasmic localization of hHDAC6 is from that of of the SE14 in LMB-resistant of hHDAC6 SE14 repeat domain is the between murine and human HDAC6 proteins this domain the cytoplasmic retention of hHDAC6, as a protein in and its localization by cytoplasmic in to the it and it in nuclear These to be is with with with actinomycin this to and of Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). shown in with to that are known to These results indicate that the SE14 repeat domain of hHDAC6 is required for LMB-resistant cytoplasmic and of hHDAC6 the cytoplasmic localization of to treatment hHDAC6 may a CRM1-dependent is to to the nucleus hHDAC6 may an with these is to nucleocytoplasmic trafficking and possesses a (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). the LMB-resistant cytoplasmic localization of hHDAC6 is to of nucleocytoplasmic trafficking signals and to the SE14 repeat domain to the cytoplasmic localization of hHDAC6, we a to sequence with is to the structural (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), is to nuclear export that this possesses nuclear and export these we the and shown in and but not treatment to nuclear accumulation of that it contains nuclear and export The treatment to of so it possesses an nuclear that an is located the Moreover, from nuclear and so the is located between and The sequence of known is J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, R. 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Nature. 1996; PubMed Scopus Google Scholar). is and as proteins and by green shown in and that is with this, a to LMB, not that the nuclear export by in a CRM1-dependent Therefore, hHDAC6 possesses two nuclear export Although in the nucleus not to in the that the SE14 repeat domain cytoplasmic retention These results suggest that and the SE14 repeat domain both to the cytoplasmic localization activity of the C-terminal of the of not an activity Therefore, with mHDAC6, hHDAC6 contains sequence the SE14 repeat domain and for cytoplasmic of HDAC6 nuclear so it possesses a Although in the nucleus cytoplasmic of the sequence of two in and lysine C. Trends Biochem. Sci. Full Text PDF PubMed Scopus Google Scholar). we of not the nuclear localization of not that is This to shown in B and in the in the to that functions as an and to the localization of with this, as with treatment not the of with the nuclear localization activity of and shown in and whereas and signals in the that and are important of nuclear so may regulate the nuclear in with The in and by green shown in and of the nuclear whereas of with the with of the nuclear localization the with with this, whereas in the of the nuclear localization and with and This is with the that nuclear The nuclear and the of these results suggest that of hHDAC6 a with this, of in its nuclear treatment not Therefore, of HDAC6 functions as an The SE14 as a results indicate that hHDAC6 possesses a unique SE14 repeat domain that is in HDAC6 proteins from C. elegans, Drosophila, mouse, and (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. 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Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), the cytoplasmic localization of hHDAC6 is LMB-resistant of regulation for the cytoplasmic localization of murine and human HDAC6 The SE14 repeat domain is required for the and is responsible for the of hHDAC6 in Moreover, to to the This displays targeting activity not Therefore, the SE14 repeat domain is a that is important for the cytoplasmic localization of HDAC6 with and the SE14 repeat domain, hHDAC6 possesses nuclear and export It has two export and 6 and and treatment with the LMB, and to the nucleus not so both and function as CRM1-dependent export is in and the has been as an (23Verdel A. Curtet S. Brocard M.P. Rousseaux S. Lemercier C. Yoshida M. Khochbin S. Curr. Biol. 2000; 10: 747-749Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). is in and the has been to be in nuclear export (23Verdel A. 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