A Novel Role of the Actin-nucleating Arp2/3 Complex in the Regulation of RNA Polymerase II-dependent Transcription

Abstract

It has been well documented that actin is present in the nucleus and involved in numerous nuclear functions including regulation of transcription. The actin-nucleating Arp2/3 complex is an essential, evolutionarily conserved seven-subunit protein complex that promotes actin cytoskeleton assembly in the cytoplasm upon stimulation by WASP family proteins. Our recent study indicates that the nuclear localized neural Wiskott-Aldrich syndrome protein (N-WASP) can induce de novo actin polymerization in the nucleus, and this function is important for the role of N-WASP in the regulation of RNA polymerase II-dependent transcription. Here, we have presented evidence to show that the Arp2/3 complex is also localized in the nucleus and plays an essential role in mediating nuclear actin polymerization induced by N-WASP. We have also demonstrated that the Arp2/3 complex physically associates with RNA polymerase II and is involved in the RNA polymerase II-dependent transcriptional regulation both in vivo and in vitro. Together, these data provide strong support for the hypothesis that N-WASP and the Arp2/3 complex regulate transcription, at least in part, through the regulation of nuclear actin polymerization in a manner similar to their function in the cytoplasm. It has been well documented that actin is present in the nucleus and involved in numerous nuclear functions including regulation of transcription. The actin-nucleating Arp2/3 complex is an essential, evolutionarily conserved seven-subunit protein complex that promotes actin cytoskeleton assembly in the cytoplasm upon stimulation by WASP family proteins. Our recent study indicates that the nuclear localized neural Wiskott-Aldrich syndrome protein (N-WASP) can induce de novo actin polymerization in the nucleus, and this function is important for the role of N-WASP in the regulation of RNA polymerase II-dependent transcription. Here, we have presented evidence to show that the Arp2/3 complex is also localized in the nucleus and plays an essential role in mediating nuclear actin polymerization induced by N-WASP. We have also demonstrated that the Arp2/3 complex physically associates with RNA polymerase II and is involved in the RNA polymerase II-dependent transcriptional regulation both in vivo and in vitro. Together, these data provide strong support for the hypothesis that N-WASP and the Arp2/3 complex regulate transcription, at least in part, through the regulation of nuclear actin polymerization in a manner similar to their function in the cytoplasm. The rapid assembly of actin filaments in the cell is required for many basic cellular processes, such as endocytosis and cell motility (1Engqvist-Goldstein A.E. Drubin D.G. Annu. Rev. Cell Dev. Biol. 2003; 19: 287-332Crossref PubMed Scopus (494) Google Scholar, 2Pollard T.D. Borisy G.G. Cell. 2003; 112: 453-465Abstract Full Text Full Text PDF PubMed Scopus (3303) Google Scholar). The Arp2/3 complex is one of the most important mediators of actin assembly. It consists of two proteins that are closely related to actin in sequence and conformation (Arp2 and Arp3) and five other proteins including p41, p34, p21, p20, and p16 in humans (3Welch M.D. DePace A.H. Verma S. Iwamatsu A. Mitchison T.J. J. Cell Biol. 1997; 138: 375-384Crossref PubMed Scopus (409) Google Scholar, 4Deeks M.J. Hussey P.J. Nat. Rev. Mol. Cell. Biol. 2005; 6: 954-964Crossref PubMed Scopus (59) Google Scholar). Many in vitro studies using purified actin show that the Arp2/3 complex is capable of initiating actin polymerization and formation of new F actin branches (4Deeks M.J. Hussey P.J. Nat. Rev. Mol. Cell. Biol. 2005; 6: 954-964Crossref PubMed Scopus (59) Google Scholar, 5Pollard T.D. J. Cell Biol. 1986; 103: 2747-2754Crossref PubMed Scopus (604) Google Scholar, 6Sept D. McCammon J.A. Biophys. J. 2001; 81: 667-674Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 7Reutzel R. Yoshioka C. Govindasamy L. Yarmola E.G. Agbandje-McKenna M. Bubb M.R. McKenna R. J. Struct. Biol. 2004; 146: 291-301Crossref PubMed Scopus (24) Google Scholar, 8Robinson R.C. Turbedsky K. Kaiser D.A. Marchand J.B. Higgs H.N. Choe S. Pollard T.D. Science. 2001; 294: 1679-1684Crossref PubMed Scopus (421) Google Scholar, 9Volkmann N. Amann K.J. Stoilova-McPhie S. Egile C. Winter D.C. Hazelwood L. Heuser J.E. Li R. Pollard T.D. Hanein D. Science. 2001; 293: 2456-2459Crossref PubMed Scopus (205) Google Scholar). This activity of the Arp2/3 complex generates space-filling networks of actin filaments that can provide the force for cell motility (10Loisel T.P. Boujemaa R. Pantaloni D. Carlier M.F. Nature. 1999; 401: 613-616Crossref PubMed Scopus (810) Google Scholar, 11Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar). The Arp2/3 complex is activated by the members of Wiskott-Aldrich syndrome protein (WASP) 2The abbreviations used are: WASP, Wiskott-Aldrich syndrome protein; N-WASP, neural WASP; VCA, verproline-cofilin-acidic; siRNA, small interfering RNA; NES, nuclear exporting sequence; HA, hemagglutinin; GFP, green fluorescent protein; BrdUrd, bromodeoxyuridine; GST, glutathione S-transferase. family, including WASP, N-WASP, and Scar/WAVE (Wasp family verprolin homologous protein) (12Linder S. Higgs H. Hufner K. Schwarz K. Pannicke U. Aepfelbacher M. J. Immunol. 2000; 165: 221-225Crossref PubMed Scopus (129) Google Scholar, 13Rohatgi R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar, 14Yarar D. To W. Abo A. Welch M.D. Curr. Biol. 1999; 9: 555-558Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 15Winter D. Lechler T. Li R. Curr. Biol. 1999; 9: 501-504Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 16Machesky L.M. Mullins R.D. Higgs H.N. Kaiser D.A. Blanchoin L. May R.C. Hall M.E. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3739-3744Crossref PubMed Scopus (617) Google Scholar). These proteins have a common C-terminal verproline-cofilin-acidic (VCA) region that can activate the Arp2/3 complex through interaction of the V domain with actin monomer and association of the CA domain with the Arp2/3 complex to induce filament formation (13Rohatgi R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar, 17Panchal S.C. Kaiser D.A. Torres E. Pollard T.D. Rosen M.K. Nat. Struct. Biol. 2003; 10: 591-598Crossref PubMed Scopus (127) Google Scholar, 18Higgs H.N. Blanchoin L. Pollard T.D. Biochemistry. 1999; 38: 15212-15222Crossref PubMed Scopus (242) Google Scholar). Despite the central function of the Arp2/3 complex in the regulation of actin filament nucleation and organization in the cytoplasm, the localization and function of the Arp2/3 complex in the nucleus have not been studied. Recent studies have shown that actin is localized in the nucleus and involved in a variety of nuclear functions (19Bettinger B.T. Gilbert D.M. Amberg D.C. Nat. Rev. Mol. Cell. Biol. 2004; 5: 410-415Crossref PubMed Scopus (219) Google Scholar, 20Pederson T. Aebi U. Mol. Biol. Cell. 2005; 16: 5055-5060Crossref PubMed Scopus (121) Google Scholar). It has been shown that the nuclear actin is associated with small nuclear ribonucleoproteins and heterogeneous nuclear ribo-nucleoproteins, which are important in the regulation of mRNA processing and the nuclear export of proteins and retroviral RNA (21Sahlas D.J. Milankov K. Park P.C. De Boni U. J. Cell Sci. 1993; 105: 347-357Crossref PubMed Google Scholar, 22Percipalle P. Zhao J. Pope B. Weeds A. Lindberg U. Daneholt B. J. Cell Biol. 2001; 153: 229-236Crossref PubMed Scopus (128) Google Scholar, 23Percipalle P. Jonsson A. Nashchekin D. Karlsson C. Bergman T. Guialis A. Daneholt B. Nucleic Acids Res. 2002; 30: 1725-1734Crossref PubMed Scopus (134) Google Scholar, 24Nakayasu H. Ueda K. Exp. Cell Res. 1985; 160: 319-330Crossref PubMed Scopus (33) Google Scholar, 25Kimura T. Hashimoto I. Yamamoto A. Nishikawa M. Fujisawa J.I. Genes Cells. 2000; 5: 289-307Crossref PubMed Scopus (72) Google Scholar, 26Hofmann W. Reichart B. Ewald A. Muller E. Schmitt I. Stauber R.H. Lottspeich F. Jockusch B.M. Scheer U. Hauber J. Dabauvalle M.C. J. Cell Biol. 2001; 152: 895-910Crossref PubMed Scopus (191) Google Scholar). The nuclear actin has also been found to attach to the nuclear pore complex in amphibian oocytes (27Kiseleva E. Drummond S.P. Goldberg M.W. Rutherford S.A. Allen T.D. Wilson K.L. J. Cell Sci. 2004; 117: 2481-2490Crossref PubMed Scopus (118) Google Scholar). It has also been found in association with the ATP-dependent chromatin remodeling complex and histone acetyltransferase complex, suggesting a potential role in chromatin remodeling (19Bettinger B.T. Gilbert D.M. Amberg D.C. Nat. Rev. Mol. Cell. Biol. 2004; 5: 410-415Crossref PubMed Scopus (219) Google Scholar, 23Percipalle P. Jonsson A. Nashchekin D. Karlsson C. Bergman T. Guialis A. Daneholt B. Nucleic Acids Res. 2002; 30: 1725-1734Crossref PubMed Scopus (134) Google Scholar, 28Olave I.A. Reck-Peterson S.L. Crabtree G.R. Annu. Rev. Biochem. 2002; 71: 755-781Crossref PubMed Scopus (356) Google Scholar). A number of recent studies have shown that the nuclear actin plays a role in the regulation of gene transcription, which is independent of its function in chromatin remodeling (29Kukalev A. Nord Y. Palmberg C. Bergman T. Percipalle P. Nat. Struct. Mol. Biol. 2005; 12: 238-244Crossref PubMed Scopus (188) Google Scholar, 30Percipalle P. Fomproix N. Kylberg K. Miralles F. Bjorkroth B. Daneholt B. Visa N. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 6475-6480Crossref PubMed Scopus (114) Google Scholar). Antibodies against actin have been shown to inhibit the transcription of naked DNA template by RNA polymerases I and II (31Hofmann W.A. Stojiljkovic L. Fuchsova B. Vargas G.M. Mavrommatis E. Philimonenko V. Kysela K. Goodrich J.A. Lessard J.L. Hope T.J. Hozak P. de Lanerolle P. Nat. Cell Biol. 2004; 6: 1094-1101Crossref PubMed Scopus (297) Google Scholar, 32Philimonenko V.V. Zhao J. Iben S. Dingova H. Kysela K. Kahle M. Zentgraf H. W.A. de Lanerolle P. Hozak P. I. Nat. Cell Biol. 2004; 6: PubMed Scopus Google Scholar). actin has been shown to for the activity of purified RNA polymerase P. S. N. Genes Dev. 2004; PubMed Scopus Google Scholar). The role of actin in transcription is by the that actin is associated with RNA polymerases (29Kukalev A. Nord Y. Palmberg C. Bergman T. Percipalle P. Nat. Struct. Mol. Biol. 2005; 12: 238-244Crossref PubMed Scopus (188) Google Scholar, W.A. Stojiljkovic L. Fuchsova B. Vargas G.M. Mavrommatis E. Philimonenko V. Kysela K. Goodrich J.A. Lessard J.L. Hope T.J. Hozak P. de Lanerolle P. Nat. Cell Biol. 2004; 6: 1094-1101Crossref PubMed Scopus (297) Google Scholar, 32Philimonenko V.V. Zhao J. Iben S. Dingova H. Kysela K. Kahle M. Zentgraf H. W.A. de Lanerolle P. Hozak P. I. Nat. Cell Biol. 2004; 6: PubMed Scopus Google Scholar, P. S. N. Genes Dev. 2004; PubMed Scopus Google Scholar, N. Percipalle P. Exp. Cell Res. 2004; 294: PubMed Scopus Google Scholar). 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Biol. 2005; Full Text Full Text PDF PubMed Scopus Google to the C-terminal of and by of by To and used for the and used for The with and and to a in the to and the used for and The with and and at the to and has been S. Takenawa T. J.L. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and Cell and polymerase II Science. and A The I and The actin polymerization actin and in with using to the and with and with and by for at and protein by protein by the cell with the for at the to by with for the complex by using as a and the for and as Y. J.L. Nat. Cell Biol. PubMed Scopus Google Scholar). by with and in a for The at for to the The at for and the the The nuclear with and in the with to the nuclear proteins. The nuclear proteins at for and the as the nuclear the actin the with for at least for as H. J.L. J. Cell Biol. 1998; PubMed Scopus Google Scholar). by fluorescent for of transcription in as L. B. J. M. J. 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Cell Biol. 2002; PubMed Scopus Google Scholar). proteins in the nucleus to of other proteins by the used in these To such a for and we to and their the of in these that both the and the of and not the of proteins the nuclear of both and upon the with with the of and found to in the nucleus of the with the not the with these that the Arp2/3 complex is localized in the nucleus, in to its The Arp2/3 in the recent studies show that the nuclear localized N-WASP induce de novo actin polymerization in the purified nuclear Y. J.L. Nat. Cell Biol. PubMed Scopus Google Scholar). its well role in mediating actin polymerization in the cytoplasm, the Arp2/3 complex localized in the nucleus also for the potential actin polymerization in the To this we the of of and the actin polymerization in the nuclear by using actin as Y. J.L. Nat. Cell Biol. PubMed Scopus Google Scholar). Y. J.L. Nat. Cell Biol. PubMed Scopus Google the of the domain of N-WASP not actin polymerization in the nuclear of in the nuclear through of the not a actin suggesting a role for the Arp2/3 complex in the the of the purified Arp2/3 complex in the nuclear the stimulation of actin polymerization by in a Together, these that the nuclear Arp2/3 complex is a of de novo actin polymerization in the of by the Arp2/3 has been that nuclear actin is important for transcriptional study that nuclear N-WASP associates with a protein complex RNA polymerase II and is involved in the regulation of RNA polymerase II transcription through its function in the polymerization of nuclear the data a role of the nuclear Arp2/3 complex in actin polymerization an for a potential function of the nuclear Arp2/3 complex in transcriptional To this we the Arp2/3 complex is also associated with RNA polymerase II by by that been with as the The with and the by to associated proteins. that RNA polymerase II in the and not To the association of and with RNA polymerase using the nuclear of with against RNA polymerase with against and of and with RNA polymerase not with These that the nuclear Arp2/3 complex also present in the complex RNA polymerase II and transcription, as shown Y. J.L. Nat. Cell Biol. PubMed Scopus Google for the nuclear N-WASP. We a potential role of the Arp2/3 complex in transcription regulation by the of of and the RNA polymerase II-dependent transcription in vivo using We the of the for transcription by RNA polymerase II by that the of is by with not with and by at which both RNA polymerase II and RNA polymerase not at which both RNA polymerase I activity not with for the gene with a protein as a We found that of by not of with the transcription activity in these A and To that the of transcription by of with for and is by a of the Arp2/3 complex the transcription not by an potential that we and in which the of the D.A. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google its have in of to the of and We also these that are to of Arp3) the and the nucleus and localized to the cytoplasm and similar to the and and localized to both the nucleus and cytoplasm We the of these to the of of and by that the of is to not is to the nucleus transcription in the using the two and These that the of of and is a and the nuclear and are for RNA polymerase II-dependent transcription. To the of of and transcription we in vitro transcription using the nuclear of RNA polymerase II and a DNA template the for the The nuclear with against protein to initiating transcription by the of DNA template and that with against not in vitro transcription. the of the purified Arp2/3 complex to the transcription for of the of transcription by these Together, these provide strong support for a role of the Arp2/3 complex in the regulation of RNA polymerase II-dependent transcription in the The actin-nucleating Arp2/3 complex is conserved in and The purified Arp2/3 complex actin-nucleating activity R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar, M.D. J. J. D.A. Mitchison T.J. Science. 1998; PubMed Scopus (421) Google and its activity is by including WASP family proteins (13Rohatgi R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. 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Science. 2001; 293: 2456-2459Crossref PubMed Scopus (205) Google Scholar, 28Olave I.A. Reck-Peterson S.L. Crabtree G.R. Annu. Rev. Biochem. 2002; 71: 755-781Crossref PubMed Scopus (356) Google Scholar, H. H. T. Welch M.D. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). this we provide evidence that the Arp2/3 complex is also localized in the nucleus and in the regulation of transcription also through its regulation of nuclear actin has been in the nucleus for many its in the nucleus has been (19Bettinger B.T. Gilbert D.M. Amberg D.C. Nat. Rev. Mol. Cell. Biol. 2004; 5: 410-415Crossref PubMed Scopus (219) Google Scholar, 28Olave I.A. Reck-Peterson S.L. Crabtree G.R. Annu. Rev. Biochem. 2002; 71: 755-781Crossref PubMed Scopus (356) Google Scholar). of evidence a role of the nuclear actin in the regulation of gene transcription, including data nuclear actin association with chromatin remodeling complex I.A. Reck-Peterson S.L. Crabtree G.R. Annu. Rev. 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PubMed Scopus Google the of the nucleus of using using the demonstrated that nuclear similar to as both and and that the actin D. C. de M.J. J. Cell Biol. PubMed Scopus Google Scholar). with these of the actin in the nucleus, we have demonstrated the nuclear function of N-WASP, a of the Arp2/3 complex in the stimulation of actin in the regulation of RNA polymerase II-dependent transcription Y. J.L. Nat. Cell Biol. PubMed Scopus Google Scholar). We found that nuclear actin polymerization is to the of the of actin such as and as well as the N-WASP of actin of nuclear actin polymerization by these mRNA transcription both in vitro and in the well function of the Arp2/3 complex in actin is that the Arp2/3 complex transcription also through its function in nuclear actin these data the that N-WASP and the Arp2/3 complex regulate transcription, at least in part, through their function in the regulation of nuclear actin in a manner similar to their function in the cytoplasm. 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