Abstract
Nuclear pore complexes (NPCs) serve as transport channels across the nuclear membrane, a double lipid bilayer that physically separates the nucleoplasm and cytoplasm of eukaryotic cells. New evidence suggests that the multiprotein nuclear pores also play a role in chromatin organization and gene expression. Given the importance of NPC function, it is not surprising that a growing list of human diseases and developmental defects have been linked to its malfunction. In order to fully understand the functional repertoire of NPCs and their essential role for nuclear organization, it is critical to determine the sequence of events that lead to the formation of nuclear pores. This is particularly relevant since NPC number, and possibly composition, are tightly linked to metabolic activity. Most of our knowledge is derived from NPC formation that occurs in dividing cells at the end of mitosis when the nuclear envelope (NE) and NPCs reform from disassembled precursors. However, NPC assembly also takes place during interphase into an intact NE. Importantly, this process is not restricted to dividing cells but also occurs during cell differentiation. Here, we will review aspects unique to this process, namely the regulation of nuclear expansion and the mechanisms of fusion between the outer and inner nuclear membranes. We will then discuss conserved and diverging mechanisms between post-mitotic and interphase assembly of the proteinaceous structure in light of recently published data.
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References
Aitchison JD, Blobel G, Rout MP (1995) Nup120p: a yeast nucleoporin required for NPC distribution and mRNA transport. J Cell Biol 131:1659–1675
Anderson DJ, Hetzer MW (2007) Nuclear envelope formation by chromatin-mediated reorganization of the endoplasmic reticulum. Nat Cell Biol 9:1160–1166
Anderson DJ, Hetzer MW (2008) Reshaping of the endoplasmic reticulum limits the rate for nuclear envelope formation. J Cell Biol 182:911–924
Antonin W (2009) Nuclear envelope: membrane bending for pore formation? Curr Biol 19:R410–R412
Antonin W, Franz C, Haselmann U, Antony C, Mattaj IW (2005) The integral membrane nucleoporin pom121 functionally links nuclear pore complex assembly and nuclear envelope formation. Mol Cell 17:83–92
Antonin W, Ellenberg J, Dultz E (2008) Nuclear pore complex assembly through the cell cycle: regulation and membrane organization. FEBS Lett 582:2004–2016
Antonny B (2006) Membrane deformation by protein coats. Curr Opin Cell Biol 18:386–394
Bastos R, Lin A, Enarson M, Burke B (1996) Targeting and function in mRNA export of nuclear pore complex protein Nup153. J Cell Biol 134:1141–1156
Bodoor K, Shaikh S, Salina D, Raharjo WH, Bastos R, Lohka M, Burke B (1999) Sequential recruitment of NPC proteins to the nuclear periphery at the end of mitosis. J Cell Sci 112(Pt 13):2253–2264
Boehmer T, Enninga J, Dales S, Blobel G, Zhong H (2003) Depletion of a single nucleoporin, Nup107, prevents the assembly of a subset of nucleoporins into the nuclear pore complex. Proc Natl Acad Sci USA 100:981–985
Brandt A, Papagiannouli F, Wagner N, Wilsch-Brauninger M, Braun M, Furlong EE, Loserth S, Wenzl C, Pilot F, Vogt N, Lecuit T, Krohne G, Grosshans J (2006) Developmental control of nuclear size and shape by Kugelkern and Kurzkern. Curr Biol 16:543–552
Brohawn SG, Schwartz TU (2009) A lattice model of the nuclear pore complex. Commun Integr Biol 2:205–207
Brohawn SG, Leksa NC, Spear ED, Rajashankar KR, Schwartz TU (2008) Structural evidence for common ancestry of the nuclear pore complex and vesicle coats. Science 322:1369–1373
Brown CR, Kennedy CJ, Delmar VA, Forbes DJ, Silver PA (2008) Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev 22:627–639
Capelson M, Liang Y, Schulte R, Mair W, Wagner U, Hetzer MW (2010) Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140:372–383
Casolari JM, Brown CR, Komili S, West J, Hieronymus H, Silver PA (2004) Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117:427–439
Chadrin A, Hess B, San Roman M, Gatti X, Lombard B, Loew D, Barral Y, Palancade B, Doye V (2010) Pom33, a novel transmembrane nucleoporin required for proper nuclear pore complex distribution. J Cell Biol 189:795–811
Chakraborty P, Wang Y, Wei JH, van Deursen J, Yu H, Malureanu L, Dasso M, Forbes DJ, Levy DE, Seemann J, Fontoura BM (2008) Nucleoporin levels regulate cell cycle progression and phase-specific gene expression. Dev Cell 15:657–667
D’Angelo MA, Anderson DJ, Richard E, Hetzer MW (2006) Nuclear pores form de novo from both sides of the nuclear envelope. Science 312:440–443
D’Angelo MA, Raices M, Panowski SH, Hetzer MW (2009) Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136:284–295
Daigle N, Beaudouin J, Hartnell L, Imreh G, Hallberg E, Lippincott-Schwartz J, Ellenberg J (2001) Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J Cell Biol 154:71–84
Dawson TR, Lazarus MD, Hetzer MW, Wente SR (2009) ER membrane-bending proteins are necessary for de novo nuclear pore formation. J Cell Biol 184:659–675
de Bruyn Kops A, Guthrie C (2001) An essential nuclear envelope integral membrane protein, Brr6p, required for nuclear transport. EMBO J 20:4183–4193
De Craene JO, Coleman J, Estrada de Martin P, Pypaert M, Anderson S, Yates JR 3rd, Ferro-Novick S, Novick P (2006) Rtn1p is involved in structuring the cortical endoplasmic reticulum. Mol Biol Cell 17:3009–3020
Debler EW, Ma Y, Seo HS, Hsia KC, Noriega TR, Blobel G, Hoelz A (2008) A fence-like coat for the nuclear pore membrane. Mol Cell 32:815–826
Dittmer TA, Richards EJ (2008) Role of LINC proteins in plant nuclear morphology. Plant Signal Behav 3:485–487
Doucet CM, Talamas JA, Hetzer MW (2010) Cell cycle-dependent differences in nuclear pore complex assembly in metazoa. Cell 141:1030–1041
Doye V, Wepf R, Hurt EC (1994) A novel nuclear pore protein Nup133p with distinct roles in poly(A) + RNA transport and nuclear pore distribution. EMBO J 13:6062–6075
Drin G, Casella JF, Gautier R, Boehmer T, Schwartz TU, Antonny B (2007) A general amphipathic alpha-helical motif for sensing membrane curvature. Nat Struct Mol Biol 14:138–146
Dultz E, Zanin E, Wurzenberger C, Braun M, Rabut G, Sironi L, Ellenberg J (2008) Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells. J Cell Biol 180:857–865
Dultz E, Huet S, Ellenberg J (2009) Formation of the nuclear envelope permeability barrier studied by sequential photoswitching and flux analysis. Biophys J 97:1891–1897
Fernandez-Martinez J, Rout MP (2009) Nuclear pore complex biogenesis. Curr Opin Cell Biol 21:603–612
Flemming D, Sarges P, Stelter P, Hellwig A, Bottcher B, Hurt E (2009) Two structurally distinct domains of the nucleoporin Nup170 cooperate to tether a subset of nucleoporins to nuclear pores. J Cell Biol 185:387–395
Franz C, Walczak R, Yavuz S, Santarella R, Gentzel M, Askjaer P, Galy V, Hetzer M, Mattaj IW, Antonin W (2007) MEL-28/ELYS is required for the recruitment of nucleoporins to chromatin and postmitotic nuclear pore complex assembly. EMBO Rep 8:165–172
Funakoshi T, Maeshima K, Yahata K, Sugano S, Imamoto F, Imamoto N (2007) Two distinct human POM121 genes: requirement for the formation of nuclear pore complexes. FEBS Lett 581:4910–4916
Gillespie PJ, Khoudoli GA, Stewart G, Swedlow JR, Blow JJ (2007) ELYS/MEL-28 chromatin association coordinates nuclear pore complex assembly and replication licensing. Curr Biol 17:1657–1662
Goldberg MW, Wiese C, Allen TD, Wilson KL (1997) Dimples, pores, star-rings, and thin rings on growing nuclear envelopes: evidence for structural intermediates in nuclear pore complex assembly. J Cell Sci 110(Pt 4):409–420
Harel A, Forbes DJ (2004) Importin beta: conducting a much larger cellular symphony. Mol Cell 16:319–330
Harel A, Chan RC, Lachish-Zalait A, Zimmerman E, Elbaum M, Forbes DJ (2003a) Importin beta negatively regulates nuclear membrane fusion and nuclear pore complex assembly. Mol Biol Cell 14:4387–4396
Harel A, Orjalo AV, Vincent T, Lachish-Zalait A, Vasu S, Shah S, Zimmerman E, Elbaum M, Forbes DJ (2003b) Removal of a single pore subcomplex results in vertebrate nuclei devoid of nuclear pores. Mol Cell 11:853–864
Heath CV, Copeland CS, Amberg DC, Del Priore V, Snyder M, Cole CN (1995) Nuclear pore complex clustering and nuclear accumulation of poly(A) + RNA associated with mutation of the Saccharomyces cerevisiae RAT2/NUP120 gene. J Cell Biol 131:1677–1697
Hetzer MW, Wente SR (2009) Border control at the nucleus: biogenesis and organization of the nuclear membrane and pore complexes. Dev Cell 17:606–616
Hetzer MW, Walther TC, Mattaj IW (2005) Pushing the envelope: structure, function, and dynamics of the nuclear periphery. Annu Rev Cell Dev Biol 21:347–380
Hinshaw JE, Milligan RA (2003) Nuclear pore complexes exceeding eightfold rotational symmetry. J Struct Biol 141:259–268
Hodge CA, Choudhary V, Wolyniak MJ, Scarcelli JJ, Schneiter R, Cole CN (2010) Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum. J Cell Sci 123:141–151
Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100:12027–12032
Kalverda B, Pickersgill H, Shloma VV, Fornerod M (2010) Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140:360–371
King MC, Lusk CP, Blobel G (2006) Karyopherin-mediated import of integral inner nuclear membrane proteins. Nature 442:1003–1007
Kiseleva E, Morozova KN, Voeltz GK, Allen TD, Goldberg MW (2007) Reticulon 4a/NogoA locates to regions of high membrane curvature and may have a role in nuclear envelope growth. J Struct Biol 160:224–235
Lau CK, Giddings TH Jr, Winey M (2004) A novel allele of Saccharomyces cerevisiae NDC1 reveals a potential role for the spindle pole body component Ndc1p in nuclear pore assembly. Eukaryot Cell 3:447–458
Li O, Heath CV, Amberg DC, Dockendorff TC, Copeland CS, Snyder M, Cole CN (1995) Mutation or deletion of the Saccharomyces cerevisiae RAT3/NUP133 gene causes temperature-dependent nuclear accumulation of poly(A) + RNA and constitutive clustering of nuclear pore complexes. Mol Biol Cell 6:401–417
Liu HL, De Souza CP, Osmani AH, Osmani SA (2009) The three fungal transmembrane nuclear pore complex proteins of Aspergillus nidulans are dispensable in the presence of an intact An-Nup84-120 complex. Mol Biol Cell 20:616–630
Lusk CP, Makhnevych T, Marelli M, Aitchison JD, Wozniak RW (2002) Karyopherins in nuclear pore biogenesis: a role for Kap121p in the assembly of Nup53p into nuclear pore complexes. J Cell Biol 159:267–278
Madrid AS, Mancuso J, Cande WZ, Weis K (2006) The role of the integral membrane nucleoporins Ndc1p and Pom152p in nuclear pore complex assembly and function. J Cell Biol 173:361–371
Makio T, Stanton LH, Lin CC, Goldfarb DS, Weis K, Wozniak RW (2009) The nucleoporins Nup170p and Nup157p are essential for nuclear pore complex assembly. J Cell Biol 185:459–473
Mansfeld J, Guttinger S, Hawryluk-Gara LA, Pante N, Mall M, Galy V, Haselmann U, Muhlhausser P, Wozniak RW, Mattaj IW, Kutay U, Antonin W (2006) The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells. Mol Cell 22:93–103
Marelli M, Lusk CP, Chan H, Aitchison JD, Wozniak RW (2001) A link between the synthesis of nucleoporins and the biogenesis of the nuclear envelope. J Cell Biol 153:709–724
Maul GG, Price JW, Lieberman MW (1971) Formation and distribution of nuclear pore complexes in interphase. J Cell Biol 51:405–418
Miao M, Ryan KJ, Wente SR (2006) The integral membrane protein Pom34p functionally links nucleoporin subcomplexes. Genetics 172:1441–1457
Oertle T, Schwab ME (2003) Nogo and its paRTNers. Trends Cell Biol 13:187–194
Olsson M, Ekblom M, Fecker L, Kurkinen M, Ekblom P (1999) cDNA cloning and embryonic expression of mouse nuclear pore membrane glycoprotein 210 mRNA. Kidney Int 56:827–838
Onischenko E, Stanton LH, Madrid AS, Kieselbach T, Weis K (2009) Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance. J Cell Biol 185:475–491
Patel SS, Rexach MF (2008) Discovering novel interactions at the nuclear pore complex using bead halo: a rapid method for detecting molecular interactions of high and low affinity at equilibrium. Mol Cell Proteomics 7:121–131
Pemberton LF, Rout MP, Blobel G (1995) Disruption of the nucleoporin gene NUP133 results in clustering of nuclear pore complexes. Proc Natl Acad Sci USA 92:1187–1191
Prufert K, Vogel A, Krohne G (2004) The lamin CxxM motif promotes nuclear membrane growth. J Cell Sci 117:6105–6116
Rafikova ER, Melikov K, Ramos C, Dye L, Chernomordik LV (2009) Transmembrane protein-free membranes fuse into xenopus nuclear envelope and promote assembly of functional pores. J Biol Chem 284:29847–29859
Rasala BA, Orjalo AV, Shen Z, Briggs S, Forbes DJ (2006) ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division. Proc Natl Acad Sci USA 103:17801–17806
Rasala BA, Ramos C, Harel A, Forbes DJ (2008) Capture of AT-rich chromatin by ELYS recruits POM121 and NDC1 to initiate nuclear pore assembly. Mol Biol Cell 19:3982–3996
Rotem A, Gruber R, Shorer H, Shaulov L, Klein E, Harel A (2009) Importin beta regulates the seeding of chromatin with initiation sites for nuclear pore assembly. Mol Biol Cell 20(18):4031–4042
Ryan KJ, McCaffery JM, Wente SR (2003) The Ran GTPase cycle is required for yeast nuclear pore complex assembly. J Cell Biol 160:1041–1053
Ryan KJ, Zhou Y, Wente SR (2006) The karyopherin Kap95 regulates nuclear pore complex assembly into intact nuclear envelopes in vivo. Mol Biol Cell 18(3):886–898
Saitoh YH, Ogawa K, Nishimoto T (2005) Brl1p—a novel nuclear envelope protein required for nuclear transport. Traffic 6:502–517
Scarcelli JJ, Hodge CA, Cole CN (2007) The yeast integral membrane protein Apq12 potentially links membrane dynamics to assembly of nuclear pore complexes. J Cell Biol 178:799–812
Sheetz MP, Painter RG, Singer SJ (1976) Biological membranes as bilayer couples III. Compensatory shape changes induced in membranes. J Cell Biol 70:193–203
Shibata Y, Voss C, Rist JM, Hu J, Rapoport TA, Prinz WA, Voeltz GK (2008) The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J Biol Chem 283:18892–18904
Siniossoglou S, Wimmer C, Rieger M, Doye V, Tekotte H, Weise C, Emig S, Segref A, Hurt EC (1996) A novel complex of nucleoporins, which includes Sec13p and a Sec13p homolog, is essential for normal nuclear pores. Cell 84:265–275
Smith S, Blobel G (1994) Colocalization of vertebrate lamin B and lamin B receptor (LBR) in nuclear envelopes and in LBR-induced membrane stacks of the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA 91:10124–10128
Snapp EL, Hegde RS, Francolini M, Lombardo F, Colombo S, Pedrazzini E, Borgese N, Lippincott-Schwartz J (2003) Formation of stacked ER cisternae by low affinity protein interactions. J Cell Biol 163:257–269
Soullam B, Worman HJ (1995) Signals and structural features involved in integral membrane protein targeting to the inner nuclear membrane. J Cell Biol 130:15–27
Stavru F, Hulsmann BB, Spang A, Hartmann E, Cordes VC, Gorlich D (2006a) NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes. J Cell Biol 173:509–519
Stavru F, Nautrup-Pedersen G, Cordes VC, Gorlich D (2006b) Nuclear pore complex assembly and maintenance in POM121- and gp210-deficient cells. J Cell Biol 173:477–483
Strambio-de-Castillia C, Niepel M, Rout MP (2010) Nat Rev Mol Cell Biol 11:490–501
Vaquerizas JM, Suyama R, Kind J, Miura K, Luscombe NM, Akhtar A (2010) Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet 6:e1000846
Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA (2006) A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124:573–586
Vollmar F, Hacker C, Zahedi RP, Sickmann A, Ewald A, Scheer U, Dabauvalle MC (2009) Assembly of nuclear pore complexes mediated by major vault protein. J Cell Sci 122:780–786
Walther TC, Alves A, Pickersgill H, Loiodice I, Hetzer M, Galy V, Hulsmann BB, Kocher T, Wilm M, Allen T, Mattaj IW, Doye V (2003a) The conserved Nup107-160 complex is critical for nuclear pore complex assembly. Cell 113:195–206
Walther TC, Askjaer P, Gentzel M, Habermann A, Griffiths G, Wilm M, Mattaj IW, Hetzer M (2003b) RanGTP mediates nuclear pore complex assembly. Nature 424:689–694
Whittle JR (2009) Schwartz TU (2009) Architectural nucleoporins Nup157/170 and Nup133 are structurally related and descend from a second ancestral element. J Biol Chem 284(41):28442–28452
Winey M, Yarar D, Giddings TH Jr, Mastronarde DN (1997) Nuclear pore complex number and distribution throughout the Saccharomyces cerevisiae cell cycle by three-dimensional reconstruction from electron micrographs of nuclear envelopes. Mol Biol Cell 8:2119–2132
Wozniak RW, Bartnik E, Blobel G (1989) Primary structure analysis of an integral membrane glycoprotein of the nuclear pore. J Cell Biol 108:2083–2092
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We would like to thank members of the Hetzer laboratory for helpful suggestions and critical reading of the manuscript. This work was supported by the NIH Ro1 GM57438.
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Doucet, C.M., Hetzer, M.W. Nuclear pore biogenesis into an intact nuclear envelope. Chromosoma 119, 469–477 (2010). https://doi.org/10.1007/s00412-010-0289-2
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DOI: https://doi.org/10.1007/s00412-010-0289-2