Molecular connections between nuclear and ciliary import processes

Cilia

Kristen J Verhey¹  H Lynn Kee¹ 

[1] Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

关键词: Size exclusion;    Ran;    Nucleoporin;    Nuclear pore complex;    Nuclear import;    Flagella;    Ciliary pore complex;    Cilia;   

Others  :  791450
DOI  :  10.1186/2046-2530-2-11

 received in 2013-05-22, accepted in 2013-07-30,  发布年份 2013

【 摘 要 】

As an organelle, the cilium contains a unique complement of protein and lipid. Recent work has begun to shed light on the mechanisms that regulate entry of ciliary proteins into the compartment. Here, we focus on the mechanisms that regulate ciliary entry of cytosolic molecules. Studies have revealed a size exclusion mechanism for ciliary entry that is similar to the barrier to nuclear entry. Active import into the ciliary compartment involves nuclear trafficking components including importins, a Ran-guanosine triphosphate gradient, and nucleoporins. Together, this work indicates that nuclei and cilia share molecular, structural and mechanistic components that regulate import into the compartments.

【 授权许可】

   
2013 Kee and Verhey; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK: The primary cilium as a complex signaling center. Curr Biol 2009, 19:R526-R535.
• [2]Oh EC, Katsanis N: Cilia in vertebrate development and disease. Development 2012, 139:443-448.
• [3]Hildebrandt F, Benzing T, Katsanis N: Ciliopathies. N Engl J Med 2011, 364:1533-1543.
• [4]Novarino G, Akizu N, Gleeson JG: Modeling human disease in humans: the ciliopathies. Cell 2011, 147:70-79.
• [5]Hou Y, Qin H, Follit JA, Pazour GJ, Rosenbaum JL, Witman GB: Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella. J Cell Biol 2007, 176:653-665.
• [6]Qin H, Diener DR, Geimer S, Cole DG, Rosenbaum JL: Intraflagellar transport (IFT) cargo: IFT transports flagellar precursors to the tip and turnover products to the cell body. J Cell Biol 2004, 164:255-266.
• [7]Nozawa YI, Lin C, Chuang PT: Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr Opin Genet Dev 2013. Epub ahead of print
• [8]Briscoe J, Therond PP: The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013, 14:418-431.
• [9]Czarnecki PG, Shah JV: The ciliary transition zone: from morphology and molecules to medicine. Trends Cell Biol 2012, 22:201-210.
• [10]Garcia-Gonzalo FR, Reiter JF: Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol 2012, 197:697-709.
• [11]Rosenbaum JL, Witman GB: Intraflagellar transport. Nat Rev Mol Cell Biol 2002, 3:813-825.
• [12]Bloodgood RA: Protein targeting to flagella of trypanosomatid protozoa. Cell Biol Int 2000, 24:857-862.
• [13]Craige B, Tsao CC, Diener DR, Hou Y, Lechtreck KF, Rosenbaum JL, Witman GB: CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. J Cell Biol 2010, 190:927-940.
• [14]Hu Q, Milenkovic L, Jin H, Scott MP, Nachury MV, Spiliotis ET, Nelson WJ: A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 2010, 329:436-439.
• [15]Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, García-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF: A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 2011, 43:776-784.
• [16]Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR: MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 2011, 192:1023-1041.
• [17]Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, Sandoval W, Peterson AS: A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 2011, 14:61-72.
• [18]Calvert PD, Schiesser WE, Pugh EN Jr: Diffusion of a soluble protein, photoactivatable GFP, through a sensory cilium. J Gen Physiol 2010, 135:173-196.
• [19]Najafi M, Maza NA, Calvert PD: Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia. Proc Natl Acad Sci U S A 2012, 109:203-208.
• [20]Najafi M, Calvert PD: Transport and localization of signaling proteins in ciliated cells. Vision Res 2012, 75:11-18.
• [21]Kee HL, Dishinger JF, Blasius TL, Liu CJ, Margolis B, Verhey KJ: A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nat Cell Biol 2012, 14:431-437.
• [22]Lin YC, Niewiadomski P, Lin B, Nakamura H, Phua SC, Jiao J, Levchenko A, Inoue T, Rohatgi R: Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nat Chem Biol 2013, 9:437-443.
• [23]Lang I, Scholz M, Peters R: Molecular mobility and nucleocytoplasmic flux in hepatoma cells. J Cell Biol 1986, 102:1183-1190.
• [24]Pante N, Kann M: Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell 2002, 13:425-434.
• [25]Mohr D, Frey S, Fischer T, Guttler T, Gorlich D: Characterisation of the passive permeability barrier of nuclear pore complexes. EMBO J 2009, 28:2541-2553.
• [26]Davis LI, Blobel G: Identification and characterization of a nuclear pore complex protein. Cell 1986, 45:699-709.
• [27]D’Angelo MA, Hetzer MW: Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol 2008, 18:456-466.
• [28]Brohawn SG, Partridge JR, Whittle JR, Schwartz TU: The nuclear pore complex has entered the atomic age. Structure 2009, 17:1156-1168.
• [29]Grossman E, Medalia O, Zwerger M: Functional architecture of the nuclear pore complex. Annu Rev Biophys 2012, 41:557-584.
• [30]Raices M, D’Angelo MA: Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Biol 2012, 13:687-699.
• [31]Alber F, Dokudovskaya S, Veenhoff LM, Zhang W, Kipper J, Devos D, Suprapto A, Karni-Schmidt O, Williams R, Chait BT, Sali A, Rout MP: The molecular architecture of the nuclear pore complex. Nature 2007, 450:695-701.
• [32]Yang Q, Rout MP, Akey CW: Three-dimensional architecture of the isolated yeast nuclear pore complex: functional and evolutionary implications. Mol Cell 1998, 1:223-234.
• [33]Hinshaw JE, Milligan RA: Nuclear pore complexes exceeding eightfold rotational symmetry. J Struct Biol 2003, 141:259-268.
• [34]Franke WW: Isolated nuclear membranes. J Cell Biol 1966, 31:619-623.
• [35]Ounjai P, Kim KD, Liu H, Dong M, Tauscher AN, Witkowska HE, Downing KH: Architectural insights into a ciliary partition. Curr Biol 2013, 23:339-344.
• [36]Beck M, Forster F, Ecke M, Plitzko JM, Melchior F, Gerisch G, Baumeister W, Medalia O: Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 2004, 306:1387-1390.
• [37]Simpson AG, Roger AJ: The real ‘kingdoms’ of eukaryotes. Curr Biol 2004, 14:R693-R696.
• [38]Wickstead B, Gull K: The evolution of the cytoskeleton. J Cell Biol 2011, 194:513-525.
• [39]Hodges ME, Wickstead B, Gull K, Langdale JA: The evolution of land plant cilia. New Phytol 2012, 195:526-540.
• [40]Devos D, Dokudovskaya S, Alber F, Williams R, Chait BT, Sali A, Rout MP: Components of coated vesicles and nuclear pore complexes share a common molecular architecture. PLoS Biol 2004, 2:e380.
• [41]Devos D, Dokudovskaya S, Williams R, Alber F, Eswar N, Chait BT, Rout MP, Sali A: Simple fold composition and modular architecture of the nuclear pore complex. Proc Natl Acad Sci U S A 2006, 103:2172-2177.
• [42]Brohawn SG, Leksa NC, Spear ED, Rajashankar KR, Schwartz TU: Structural evidence for common ancestry of the nuclear pore complex and vesicle coats. Science 2008, 322:1369-1373.
• [43]DeGrasse JA, DuBois KN, Devos D, Siegel TN, Sali A, Field MC, Rout MP, Chait BT: Evidence for a shared nuclear pore complex architecture that is conserved from the last common eukaryotic ancestor. Mol Cell Proteomics 2009, 8:2119-2130.
• [44]van Dam TJ, Townsend MJ, Turk M, Schlessinger A, Sali A, Field MC, Huynen MA: Evolution of modular intraflagellar transport from a coatomer-like progenitor. Proc Natl Acad Sci U S A 2013, 110:6943-6948.
• [45]Jekely G, Arendt D: Evolution of intraflagellar transport from coated vesicles and autogenous origin of the eukaryotic cilium. Bioessays 2006, 28:191-198.
• [46]Neumann N, Lundin D, Poole AM: Comparative genomic evidence for a complete nuclear pore complex in the last eukaryotic common ancestor. PLoS One 2010, 5:e13241.
• [47]Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH: Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem 2007, 282:5101-5105.
• [48]Lee BJ, Cansizoglu AE, Suel KE, Louis TH, Zhang Z, Chook YM: Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell 2006, 126:543-558.
• [49]Dishinger JF, Kee HL, Jenkins PM, Fan S, Hurd TW, Hammond JW, Truong YN, Margolis B, Martens JR, Verhey KJ: Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol 2010, 12:703-710.
• [50]Hurd TW, Fan S, Margolis BL: Localization of retinitis pigmentosa 2 to cilia is regulated by Importin beta2. J Cell Sci 2011, 124:718-726.
• [51]Fan S, Fogg V, Wang Q, Chen XW, Liu CJ, Margolis B: A novel Crumbs3 isoform regulates cell division and ciliogenesis via importin beta interactions. J Cell Biol 2007, 178:387-398.
• [52]Fan S, Whiteman EL, Hurd TW, McIntyre JC, Dishinger JF, Liu CJ, Martens JR, Verhey KJ, Sajjan U, Margolis B: Induction of Ran GTP drives ciliogenesis. Mol Biol Cell 2011, 22:4539-4548.
• [53]Ludington WB, Wemmer KA, Lechtreck KF, Witman GB, Marshall WF: Avalanche-like behavior in ciliary import. Proc Natl Acad Sci U S A 2013, 110:3925-3930.
• [54]Gorlich D, Kutay U: Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 1999, 15:607-660.
• [55]Ciliary proteome database http://v3.ciliaproteome.org/cgi-bin/index.php webcite
• [56]Gherman A, Davis EE, Katsanis N: The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet 2006, 38:961-962.
• [57]Kierszenbaum AL, Gil M, Rivkin E, Tres LL: Ran, a GTP-binding protein involved in nucleocytoplasmic transport and microtubule nucleation, relocates from the manchette to the centrosome region during rat spermiogenesis. Mol Reprod Dev 2002, 63:131-140.
• [58]Clarke PR, Zhang C: Spatial and temporal coordination of mitosis by Ran GTPase. Nat Rev Mol Cell Biol 2008, 9:464-477.
• [59]Wilkinson KA, Henley JM: Mechanisms, regulation and consequences of protein SUMOylation. Biochem J 2010, 428:133-145.
• [60]Palancade B, Doye V: Sumoylating and desumoylating enzymes at nuclear pores: underpinning their unexpected duties? Trends Cell Biol 2008, 18:174-183.
• [61]Li Y, Zhang Q, Wei Q, Zhang Y, Ling K, Hu J: SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptors. J Cell Biol 2012, 199:589-598.
• [62]Maiuri T, Woloshansky T, Xia J, Truant R: The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal. Hum Mol Genet 2013, 22:1383-1394.
• [63]Morris RL, English CN, Lou JE, Dufort FJ, Nordberg J, Terasaki M, Hinkle B: Redistribution of the kinesin-II subunit KAP from cilia to nuclei during the mitotic and ciliogenic cycles in sea urchin embryos. Dev Biol 2004, 274:56-69.
• [64]Fischer T, Rodriguez-Navarro S, Pereira G, Racz A, Schiebel E, Hurt E: Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery. Nat Cell Biol 2004, 6:840-848.
• [65]Resendes KK, Rasala BA, Forbes DJ: Centrin 2 localizes to the vertebrate nuclear pore and plays a role in mRNA and protein export. Mol Cell Biol 2008, 28:1755-1769.
• [66]Pan YR, Lee EY: UV-dependent interaction between Cep164 and XPA mediates localization of Cep164 at sites of DNA damage and UV sensitivity. Cell Cycle 2009, 8:655-664.
• [67]Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, et al.: The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006, 38:674-681.
• [68]Sivasubramaniam S, Sun X, Pan YR, Wang S, Lee EY: Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Genes Dev 2008, 22:587-600.
• [69]Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, et al.: Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 2012, 150:533-548.
• [70]Chatel G, Fahrenkrog B: Nucleoporins: leaving the nuclear pore complex for a successful mitosis. Cell Signal 2011, 23:1555-1562.
• [71]Wozniak R, Burke B, Doye V: Nuclear transport and the mitotic apparatus: an evolving relationship. Cell Mol Life Sci 2010, 67:2215-2230.
• [72]Delaval B, Bright A, Lawson ND, Doxsey S: The cilia protein IFT88 is required for spindle orientation in mitosis. Nat Cell Biol 2011, 13:461-468.
• [73]Wood CR, Wang Z, Diener D, Zones JM, Rosenbaum J, Umen JG: IFT proteins accumulate during cell division and localize to the cleavage furrow in Chlamydomonas. PLoS One 2012, 7:e30729.
• [74]Finetti F, Paccani SR, Riparbelli MG, Giacomello E, Perinetti G, Pazour GJ, Rosenbaum JL, Baldari CT: Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat Cell Biol 2009, 11:1332-1339.