リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Studies on the mechanism of ciliary protein localization and the molecular basis of ciliopathies」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Studies on the mechanism of ciliary protein localization and the molecular basis of ciliopathies

QIU, HANTIAN 京都大学 DOI:10.14989/doctor.k23474

2021.09.24

概要

動物のほとんどの細胞には、繊毛という細胞膜から突出するアンテナ状のオルガネラが存在する。繊毛膜にはさまざまな受容体やイオンチャネルが局在し、外部刺激の受容やヘッジホッグなどのシグナルの伝達に関与する。繊毛の異常は、嚢胞腎、網膜変性、病的肥満、多指など多様な重篤症状を呈する「繊毛病」と総称される遺伝性疾患を引き起こす。

受容体等のタンパク質の繊毛内での輸送は、IFT(intraflagellar transport)装置によって媒介される。IFT装置は、IFT-A複合体、IFT-B複合体、BBSome複合体、およびモータータンパク質のキネシン2とダイニン2から構成される。IFT-B複合体はキネシン2と共役して、繊毛内でのタンパク質の順行輸送を担い、IFT-A複合体はダイニン2と共役して繊毛内逆行輸送を担う。しかし、IFT装置と繊毛タンパク質との相互作用や機能的な関連性、繊毛病の分子基盤には不明点が多い。そこで、繊毛内タンパク質輸送機構を解明し、繊毛病の発症機構の理解につなげるために、以下の研究を行った。

第一章 ホスホイノシチドホスファターゼINPP5Eの繊毛膜への局在機構
繊毛病ジュベール症候群の原因遺伝子によってコードされるINPP5Eは、繊毛膜に局在するホスホイノシチドホスファターゼであり、繊毛膜に存在するPI(4,5)P2 を脱リン酸化して PI(4)Pへと変換する。繊毛膜をPI(4)Pが豊富な環境にすることによって、さまざまなタンパク質の繊毛膜への局在を制御すると考えられている。しかし、INPP5E自体の繊毛局在機構が不明だったので、以下の研究を行った。

まず、著者はCRISPR/Cas9システムを用いてINPP5Eノックアウト( KO)細胞を樹立して表現型を解析した。INPP5E-KO細胞において、IFT88(IFT-B複合体のサブユニット)やIFT140(IFT-A複合体のサブユニット)は繊毛内一様に蓄積する異常を示し、ヘッジホッグシグナル依存的に繊毛から排出されるGPCRであるGPR161が繊毛から全く排出されなくなった。これらの結果から、INPP5Eは,繊毛膜でのPI(4,5)P2からPI(4)Pへの変換を介して、IFT装置の運動を制御することが示唆された。

INPP5Eは、C末端付近に存在する繊毛局在化配列(CTS)を介して、ARF-ARLファミリーに属する低分子量GTPaseのARL13Bと相互作用できること、ARL13B-KO細胞ではINPP5Eが繊毛に局在できなくなることが、所属研究室の先行研究でわかっている。ARL13B-KO細胞とINPP5E-KO細胞の表現型を比較すると、繊毛内のIFT88やIFT140の蓄積の程度が異なることが分かった。また、ARL13Bと相互作用できないINPP5E(∆CTS)変異体をINPP5E-KO細胞で発現させると、INPP5E(∆CTS)は繊毛内に局在できないにもかかわらず、IFT装置の異常な蓄積やGPR161の排出不全を回復させた。これらの結果から、INPP5Eの機能に関して、INPP5Eが恒常的に繊毛に局在することは決定的な要因ではないと考えられた。

INPP5EとARL13Bの相互作用がない場合に、INPP5Eは繊毛内に進入できても、繊毛膜に保持されない可能性がある。そこで著者は、ラパマイシンにより制御可能な化学誘導性二量体形成法(FKBP-FRB実験系)を用いて、INPP5Eの繊毛局在を人為的に制御する実験を行った。その結果、INPP5EはCTSを介してARL13Bと結合しなくても、またARL13B自体が存在しない場合でも、繊毛内に進入することはできるが、INPP5EとARL13Bとの間の相互作用がなければ、繊毛膜上に留まることができないことが明らかになった。

以上の結果から、INPP5EのARL13Bとの結合は、INPP5Eが繊毛膜にとどまるためには必須であるが、繊毛内への進入にとっては必須ではないことが示された。

第二章 ダイニン2複合体中間軽鎖DYNC2LI1の変異に起因する繊毛病の分子基盤
ダイニン2複合体は、繊毛内タンパク質輸送においてIFT装置の繊毛先端から根元への逆行輸送の モーターとして働いている。ダイニン2 複合体の 11 種類のサブユニット( 重鎖 DYNC2H1、中間軽鎖DYNC2LI1、中間鎖WDR34、WDR60、軽鎖DYNLL1/2 DYNLRB1/2、DYNLT1/3、TCTEX1D2)のうち、下線で示すダイニン2複合体に特異的な5つのサブユニットは、繊毛病のSRTD(短肋骨性胸郭異形成症)、JATD(窒息性胸郭異形成症)の原因遺伝子によってコードされている。先行研究によって、DYNC2LI1の複合ヘテロ接合性変異(1–317とP120S、Δ302–332とL117V、および1–207とT221I)が、短肋骨多指症候群(SRPS、SRTD15)の原因であることが報告されている。これら3種類の複合ヘテロ接合性変異に起因する病態の分子基盤を解明するために、以下の研究を行った。

まず、著者はDYNC2LI1の野生型および各変異体とダイニン2の他のサブユニットとの相互作用を共免疫沈降法によって調べた。DYNC2LI1(T221I)を除くすべての変異体に関して、 DYNC2H1およびWDR60との相互作用が減弱したのに対して、DYNC2LI1のいずれの変異も WDR34との相互作用には影響を及ぼさなかった。

次に著者は、DYNC2LI1-KO細胞に各変異体を安定発現させるレスキュー実験を行い、それらの表現型を調べた。DYNC2LI1(1–317)、DYNC2LI1(Δ302–332)、およびDYNC2LI1(1–207)の三つの欠失変異体は、DYNC2LI1-KO細胞の繊毛形成不全やIFT装置の異常な繊毛内蓄積などの表現型をレスキューできなかった。一方、DYNC2LI1(P120S)、DYNC2LI1(L117V)、およびDYNC2LI1(T221I)の三つの点変異体は、いずれもDYNC2LI1-KO細胞の異常な表現型をレスキューした。さらに、繊毛病患者の遺伝子型を模倣して、DYNC2LI1ヘテロ接合体の組合 せ を共 発現 させた 細 胞の 表現 型を解 析 した 。その結果 、 DYNC2LI1(1–317) と DYNC2LI1(P120S)の組合せ、およびDYNC2LI1(Δ302–332)とDYNC2LI1(L117V)の組合せを共発現させた細胞では、異常な表現型がレスキューされないことがわかった。

以上の結果から、短肋骨多指症候群の患者で見られるDYNC2LI1の複合ヘテロ接合性変異が、繊毛機能の異常を引き起こす分子基盤であることを明らかにすることができた。

この論文で使われている画像

参考文献

Arts, H., and Knoers, N. (2013 [updated 2018]). Cranioectodermal dysplasia. In: GeneReviews® [Internet], eds. M.P. Adam, H.H. Ardinger, R.A. Pagon, S.E. Wallace, L.J.H. Bean, K. Stephens, and A. Amemiya, Seatle (WA): University of Washington. Asante, D., Stevenson, N.L., and Stephens, D.J. (2014). Subunit composition of the human cytoplasmic dynein-2 complex. J. Cell Sci. 127, 4774-4787.

Badgandi, H. B., Hwang, S., Shimada, I. S., Loriot, E. and Mukhopadhyay, S. (2017). Tubby family proteins are adaptors for ciliary trafficking of integral membrane proteins. J. Cell Biol. 216, 743-760.

Bangs, F. and Anderson, K. V. (2017). Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. 9, a028175.

Berbari, N. F., Johnson, A. D., Lewis, J. S., Askwith, C. C. and Mykytyn, K. (2008). Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol. Biol. Cell 19, 1540-1547.

Bielas, S. L., Silhavy, J. L., Brancati, F., Kisseleva, M. V., Al-Gazali, L., Sztriha, L., Bayoumi, R. A., Zaki, M. S., Abdel-Aleem, A., Rosti, R. O. et al. (2009). Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat. Genet. 41, 1032-1036.

Braun, D. A. and Hildebrandt, F. (2017). Ciliopathies. Cold Spring Harb. Perspect. Biol. 9, a028191

Bredrup, C., Saunier, S., Oud, M.M., Piskerstrand, T., Hoischen, A., Brackman, D., Leh, S.M., Midtbø, M., Filhol, E., Bole-Feysot, C., Nitschké, P., Gilissen, C., Haugen, O.H., Sanders, J.-S.F., Stolte-Dijkstra, I., Mans, D.A., Steenbergen, E.J., Hamel, B.C.J., Matignon, M., Pfundt, R., Jeanpierre, C., Boman, H., Rødahl, E., Veltman, J.A., Knappskog, P.M., Knoers, N.V.A.M., Roepman, R., and Arts, H.H. (2011). Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am. J. Hum. Genet. 89, 634-643.

Breslow, D. K., Koslover, E. F., Seydel, F., Spakowitz, A. J. and Nachury, M. V. (2013). An in vitro assay for entry into cilia reveals unique properties of the soluble diffusion barrier. J. Cell Biol. 203, 129-147.

Briscoe, J. and Thérond, P. P. (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416-429.

Chávez, M., Ena, S., Van Sande, J., de Kerchove d'Exaerde, A., Schurmans, S. and Schiffmann, S. N. (2015). Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev. Cell 34, 338-350.

Conduit, S. E. and Vanhaesebroeck, B. (2020). Phosphoinositide lipids in primary cilia biology. Biochem. J. 477, 3541-3565.

Corés, C.R., Metzis, V., and Wicking, C. (2015). Unmasking the ciliopathies: craniofacial defects and the primary cilium. Wiley Interdiscip. Rev. Dev. Biol. 4, 637-653.

Coussa, R.G., Otto, E.A., Gee, H.-Y., Arthurs, P., Ren, H., Lopez, I., Keser, V., Fu, Q., Faingold, R., Khan, A.H., Schwartzentruber, J., Majewski, J., Hildebrandt, F., and Koenekoop, R.K. (2013). WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigentosa and in Senior-Loken syndrome. Clin. Genet. 84, 150-159.

Dutta, N. and Seo, S. (2016). RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-depenent manner. Biol. Open 5, 1283-1289.

Dyson, J. M., Conduit, S. E., Feeney, S. J., Hakim, S., DiTommaso, T., Fulcher, A. J., Sriratana, A., Ramm, G., Horan, K. A., Gurung, R. et al. (2017). INPP5E regulates phosphoinositide-dependent cilia transition zone function. J. Cell Biol. 216, 247-263.

Eguether, T., San Agustin, J. T., Keady, B. T., Jonassen, J. A., Liang, Y., Francis, R., Tobita, K., Johnson, C. A., Abdelhamed, Z. A., Lo, C. W. et al. (2014). IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev. Cell 21, 279-290.

Fansa, E. K. and Wittinghofer, A. (2016). Sorting of lipidated cargo by the Arl2/Arl3 system. Small GTPases 7, 222-230.

Fansa, E. K., Kösling, S. K., Zent, E., Wittinghofer, A. and Ismail, S. (2016). PDE6δ- mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat. Commun. 7, 11366.

Fisher, S., Kuna, D., Caspary, T., Kahn, R. A. and Sztul, E. (2020). ARF family GTPases with links to cilia. Am. J. Physiol. Cell Physiol. 319, C404-C418.

Garcia-Gonzalo, F. R. and Reiter, J. F. (2017). Open sesame: how transition fibers and the transition zone control ciliary composition. Cold Spring Harb. Perspect. Biol. 9, a028134.

Garcia-Gonzalo, F. R., Phua, S. C., Roberson, E. C., Garcia, G., III, Abedin, M., Schurmans, S., Inoue, T. and Reiter, J. F. (2015). Phosphoinositides regulate ciliary protein trafficking to modulate Hedgehog signaling. Dev. Cell 34, 400- 409.

Gigante, E. D. and Caspary, T. (2020). Signaling in the primary cilum through the lens of the Hedgehog pathway. Wiley Interdiscip. Rev. Dev. Biol. 9, e377.

Gigante, E. D., Taylor, M. R., Ivanova, A. A., Kahn, R. A. and Caspary, T. (2020). ARL13B regulates sonic hedgehog signaling from outside primary cilia. eLife 9, e50434.

Gonçalves, J. and Pelletier, L. (2017). The ciliary transition zone: finding the pieces and assembling the gate. Mol. Cells 40, 243-253.

Gotthardt, K., Lokaj, M., Koerner, C., Falk, N., Gießl, A. and Wittinghofer, A. (2015). A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins. eLife 4, e11859.

Haeussler, M., Schönig, K., Eckert, H., Eschstruth, A., Mianné, J., Renaud, J.B., Schneider-Maunoury, S., Shkumatava, A., Teboul, L., Kent, J., Joly, J.S., and Concordet, J.P. (2016). Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol. 17, 148.

Hamada, Y., Tsurumi, Y., Nozaki, S., Katoh, Y., and Nakayama, K. (2018). Interaction of WDR60 intermediate chain with TCTEX1D2 light chain of the dynein-2 complex is crucial for ciliary protein trafficking. Mol. Biol. Cell 29, 1628-1639.

Hasegawa, J., Iwamoto, R., Otomo, T., Nezu, A., Hamasaki, M. and Yoshimori, T. (2016). Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. EMBO J. 35, 1853-1867.

Higginbotham, H., Eom, T.-Y., Mariani, L. E., Bachleda, A., Hirt, J., Gukassyan, V., Cusack, C. L., Lai, C., Caspary, T. and Anton, E. S. (2012). Arl13b in primary cilia regulates the migration and placement of interneurons in the developing cerebral cortex. Dev. Cell 23, 925-938.

Hirano, T., Katoh, Y. and Nakayama, K. (2017). Intraflagellar transport-A complex mediates ciliary entry as well as retrograde trafficking of ciliary G protein- coupled receptors. Mol. Biol. Cell 28, 429-439.

Hirokawa, N., Niwa, S., and Tanaka, Y. (2010). Molecular motors in neurons: transport mechanisms and roles in brain functiion, development, and disease. Neuron 68, 610-638.

Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C. and Seo, S. (2012). ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc. Natl. Acad. Sci. USA 109, 19691-19696.

Ishida, Y., Kobayashi, T., Chiba, S., Katoh, Y., and Nakayama, K. (2021). Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia. Hum. Mol. Genet. 30, 213-225.

Ishikawa, H., and Marshall, W.F. (2011). Ciliogenesis: building the cell's antenna. Nat. Rev. Mol. Cell Biol. 12, 222-234.

Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. and Wittinghofer, A. (2011). Arl2-GTP and Arl3-GTP regulates a GDI-like transport system for farnesylated cargo. Nat. Chem. Biol. 7, 942-949.

Ivanova, A. A., Caspary, T., Syfriend, N. T., Duong, D. M., West, A. B., Liu, Z. and Kahn, R. A. (2017). Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF). J. Biol. Chem. 292, 11091-11108.

Jensen, V. L. and Leroux, M. R. (2017). Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment. Curr. Opin. Cell Biol. 47, 83-91.

Jensen, V.L., Lambacher, N.J., Li, C., Mohan, S., Williams, C.L., Inglis, P.N., Yoder, B.K., Blacque, O.E., and Leroux, M.R. (2018). Role for intraflagellar transport in building a functional transition zone. EMBO Rep. 19, e45862.

Jordan, M.A., Diener, D.R., Stepanek, L., and Pigino, G. (2018). The cryo-EM structure of intraflagellar transport trains reveals how dynein is inactivated to ensure unidirectional anterogarde movement in cilia. Nat. Cell Biol. 20, 1250-1255.

Katoh, Y., Chiba, S. and Nakayama, K. (2020). Practical method for superresolution imaging of primary cilia and centrioles by expansion microscopy using an amplibody for fluorescence signal amplification. Mol. Biol. Cell 31, 2195–2206.

Katoh, Y., Michisaka, S., Nozaki, S., Funabashi, T., Hirano, T., Takei, R. and Nakayama, K. (2017). Practical method for targeted disruption of cilia-related genes by using CRISPR/Cas9-mediated homology-independent knock-in system. Mol. Biol. Cell 28, 898-906.

Katoh, Y., Nakamura, K. and Nakayama, K. (2018). Visible immunoprecipitation (VIP) assay: a simple and versatile method for visual detection of protein-protein interactions. Bio-protocol 8, e2687.

Katoh, Y., Nozaki, S., Hartanto, D., Miyano, R. and Nakayama, K. (2015). Architectures of multisubunit complexes revealed by a visible immunoprecipitation assay using fluorescent fusion proteins. J. Cell Sci. 128, 2351-2362.

Katoh, Y., Terada, M., Nishijima, Y., Takei, R., Nozaki, S., Hamada, H., and Nakayama, K. (2016). Overall architecture of the intraflagellar transport (IFT)-B complex containing Cluap1/IFT38 as an essential component of the IFT-B peripheral subcomplex. J. Biol. Chem. 291, 10962-10975.

Kee, H. L., Dishinger, J. F., Blasius, T. L., Liu, C.-J., Margolis, B. and Verhey, K. J. (2012). A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nat. Cell Biol. 14, 431-437.

Kessler, K., Wunderlich, I., Uebe, S., Falk, N.S., Gießl, A., Brandstätter, J.H., Popp, B., Klinger, P., Ekici, A.B., Sticht, H., Dörr, H.G., Reis, A., Roepman, R., Seemanová, E., and Thiel, C.T. (2015). DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects. Sci. Rep. 5, 11649.

Kobayashi, T., Ishida, Y., Hirano, T., Katoh, Y. and Nakayama, K. (2021). Cooperation of the IFT-A complex with the IFT-B complex is required for ciliary retrograde protein trafficking and GPCR import. Mol. Biol. Cell 32, 45-56.

Komatsu, T., Kukelyansky, I., McCaffery, J. M., Ueno, T., Varela, L. C. and Inoue, T. (2010). Organelle-specific, rapid induction of molecular activities and membrane tethering. Nat. Methods 7, 206-208.

Kong, A. M., Horan, K. A., Sriratana, A., Bailey, C. G., Collyer, L. J., Nandurkar, H. H., Shisheva, A., Layton, M. J., Rasko, J. E. J., Rowe, T. et al. (2006). Phosphatidylinositol 3-phosphate [PtdIns(3)P] is generated at the plasma membrane by an inositol polyphosphate 5-phosphatase: endogenous PtdIns(3)P can promote GLUT4 translocation to the plasma membrane. Mol. Cell. Biol. 26, 6065-6081.

Kopinke, D., Norris, A.M., and Mukhopadhyay, S. (2021). Developmental and regenerative paradigms of cilia regulated hedgehog signaling. Sem. Cell Dev. Biol. 110, 89-103.

Kösling, S. K., Fansa, E. K., Maffini, S. and Wittinghofer, A. (2018). Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment. Biol. Chem. 399, 277-292.

Lechtreck, K.-F., Brown, J. M., Sampaio, J. L., Craft, J. M., Shevchenko, A., Evans, J. E. and Witman, G. B. (2013). Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase. J. Cell Biol. 201, 249-261.

Liew, G. M., Ye, F., Nager, A. R., Murphy, J. P., Lee, J. S. H., Aguiar, M., Breslow, D. K., Gygi, S. P. and Nachury, M. V. (2014). The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev. Cell 31, 265-278.

Lin, A.E., Traum, A.Z., Sahai, I., Keppler-Noreuil, K., Kukolich, M.K., Adam, M.P., Westra, S.J., and Arts, H.H. (2013). Sensenbrenner syndrome (Cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients. Am. J. Med. Genet. 161A, 2762-2776.

Lin, Y.-C., Niewiadomski, P., Lin, B., Nakamura, H., Phua, S. C., Jiao, J., Levchenko, A., Inoue, T., Rohatgi, R. and Inoue, T. (2013). Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nat. Chem. Biol. 9, 437-443.

Liu, P. and Lechtreck, K. F. (2018). The Bardet-Biedl syndrome protein complex is an adaptor expanding the cargo of range of intraflagellar transport trains for ciliary export. Proc. Natl. Acad. Sci. USA 115, E934-E943.

Madhivanan, K. and Aguilar, R. C. (2014). Ciliopathies: the trafficking connection. Traffic 15, 1031-1056.

McInerney-Leo, A.M., Harris, J.E., Marshall, M.S., Gardiner, B., Kinning, E., Leong, H.Y., McKenzie, F., Ong, W.P., Vodopiutz, J., Wicking, C., Brown, M.A., Zankl, A., and Duncan, E.L. (2015). Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies. Clin. Genet. 88, 550-557.

Mitchison, H.M., and Valente, E.M. (2017). Motile and non-motile cilia in human pathology: from function to phenotypes. J. Pathol. 241, 294-309.

Motohashi, K. (2015). A simple and efficient seamless DNA cloning method using SLiCE from Escherichia coli laboratory strains and its application to SLiP site-directed mutagenesis. BMC Biotechnol. 15, 47.

Mukhopadhyay, S. and Rohatgi, R. (2014). G-protein-coupled receptors, Hedgehog signaling and primary cilia. Sem. Cell Dev. Biol. 33, 63-72.

Mukhopadhyay, S., Badgandi, H.B., Hwang, S.-H., Somatilaka, B., Shimada, I.S., and Pal, K. (2017). Trafficking to the primary cilium membrane. Mol. Biol. Cell 28, 233-239.

Mukhopadhyay, S., Wen, X., Chih, B., Nelson, C. D., Lane, W. S., Scales, S. J. and Jackson, P. K. (2010). TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 24, 2180-2193.

Nachury, M. V. and Mick, D. U. (2019). Establishing and regulating the composition of cilia for signal transduction. Nat. Rev. Mol. Cell Biol. 20, 389-405.

Nagata, A., Hamamoto, A., Horikawa, M., Yoshimura, K., Takeda, S. and Saito, Y. (2013). Characterization of ciliary targeting sequence of rat melanin-concentrating hormone receptor 1. Gen. Comp. Endocrinol. 188, 159-165.

Nakatsu, F. (2015). A phosphoinositide code for primary cilia. Dev. Cell 34, 379-380.

Nakayama, K. and Katoh, Y. (2020). Architecture of the IFT ciliary trafficking machinery and interplay between its components. Crit. Rev. Biochem. Mol. Biol. 55, 179- 196.

Nakayama, K., and Katoh, Y. (2018). Ciliary protein trafficking mediated by IFT and BBSome complexes with the aid of kinesin-2 and dynein-2 motors. J. Biochem. 163, 155-164.

Niceta, M., Margiotti, K., Digilio, M.C., Guida, V., Bruselles, A., Pizzi, S., Ferraris, A., Memo, L., Laforgia, N., Dentici, M.L., Consoli, F., Torrente, I., Ruiz-Perez, V.L., Dallapiccola, B., Marino, B., De Luca, A., and Tartaglia, M. (2018). Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome. Clin. Genet. 93, 632-639.

Nishijima, Y., Hagiya, Y., Kubo, T., Takei, R., Katoh, Y. and Nakayama, K. (2017). RABL2 interacts with the intraflagellar transport B complex and CEP19 and participates in ciliary assembly. Mol. Biol. Cell 28, 1652-1666.

Nozaki, S., Castro Araya, R. F., Katoh, Y. and Nakayama, K. (2019). Requirement of IFT- B–BBSome complex interaction in export of GPR161 from cilia. Biol. Open 8, bio043786.

Nozaki, S., Katoh, Y., Kobayashi, T. and Nakayama, K. (2018). BBS1 is involved in retrograde trafficking of ciliary GPCRs in the context of the BBSome complex. PLoS One 13, e0195005.

Nozaki, S., Katoh, Y., Terada, M., Michisaka, S., Funabashi, T., Takahashi, S., Kontani, K. and Nakayama, K. (2017). Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. J. Cell Sci. 130, 563- 576.

Okazaki, M., Kobayashi, T., Chiba, S., Takei, R., Liang, L., Nakayama, K. and Katoh, Y. (2020). Formation of the B9-domain protein complex MKS1–B9D2–B9D1 is essential as a diffusion barrier for ciliary membrane proteins. Mol. Biol. Cell 31, 2259–2268.

Parisi, M. and Glass, I. (2003 [updated 2017]). Joubert syndrome. In GeneReviews® [Internet], (eds. M. P. Adam H. H. Ardinger R. A. Pagon S. E. Wallace L. J. H. Bean K. Stephens and A. Amemiya). Seatle (WA): University of Washington.

Park, J., Lee, J., Shim, J., Han, W., Lee, J., Bae, Y. C., Chung, Y. D., Kim, C. H. and Moon, S. J. (2013). dTULP, the Drosophila melanogaster homolog of Tubby, regulates transient receptor potential channel localization in cilia. PLoS Genet. 9, e1003814.

Phua, S. C., Chiba, S., Suzuki, M., Su, E., Roberson, E. C., Pusapati, G. V., Setou, M., Rohatgi, R., Reiter, J. F., Ikegami, K. et al. (2017). Dynamic remodeling of membrane composition drives cell cycle through primary cilia excision. Cell 168, 264-279.

Prevo, B., Scholey, J.M., and Peterman, E.J.G. (2017). Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. FEBS J. 284, 2905-2931.

Qiu, H., Fujisawa, S., Nozaki, S., Katoh, Y., and Nakayama, K. (2021). Interaction of INPP5E with ARL13B is essential for its ciliary membrane retention but dispensable for its ciliary entry. Biol. Open 10, bio057653.

Reiter, J. F. and Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18, 533-547.

Rosenbaum, J.L., and Witman, G.B. (2002). Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 3, 813-825

Scheidel, N., and Blacque, O. (2018). Intraflagellar transport complex A genes differentially regulate cilium formation and transition zone gating. Curr. Biol. 28, 3279-3287.

Schmidts, M. (2014). Clinical genetics and pathobiology of ciliary chondrodysplasias. J. Pediatr. Genet. 3, 49-64.

Schroeder, C.M., Ostrem, J.M.L., Hertz, N.T., and Vale, R.D. (2014). A Ras-like domain in the light intermediate chain bridges the dynein motor eLife 3, e03351.

Stephen, L. A. and Ismail, S. (2016). Shuttling and sorting of lipid-modified cargo into the cilia. Biochem. Soc. Trans. 44, 1273-1280.

Sung, C.-H. and Leroux, M. R. (2013). The roles of evolutionarily conserved functional modules in cilia-related trafficking. Nat. Cell Biol. 15, 1387-1397.

Takada, N., Naito, T., Inoue, T., Nakayama, K., Takatsu, H. and Shin, H.-W. (2018). Phospholipid-flipping activity of P4-ATPase drives membrane curvature. EMBO J. 37, e97705.

Takahara, M., Katoh, Y., Nakamura, K., Hirano, T., Sugawa, M., Tsurumi, Y., and Nakayama, K. (2018). Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Hum. Mol. Genet. 27, 516-528.

Takahashi, S., Kubo, K., Waguri, S., Yabashi, A., Shin, H.-W., Katoh, Y. and Nakayama, K. (2012). Rab11 regulates exocytosis of recycling vesicles at the plasma membrane. J. Cell Sci. 125, 4049-4057.

Takao, D. and Verhey, K. J. (2016). Gated entry into the ciliary compartment. Cell. Mol. Life Sci. 73, 119-127.

Taschner, M. and Lorentzen, E. (2016). The intraflagellar transport machinery. Cold Spring Harb. Perspect. Biol. 8, a028092.

Taylor, S.P., Dantas, T.J., Duran, I., Wu, S., Lachman, R.S., Consortium, U.o.W.C.f.M.G., Nelson, S.F., Cohn, D.H., Vallee, R.B., and Krakow, D. (2015). Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. Nat. Commun. 6, 7092.

Thomas, S., Ritter, B., Verbich, D., Sanson, C., Bourbonnière, L., McKinney, R. A. and McPherson, P. S. (2009). Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons. J. Biol. Chem. 284, 12410-12419.

Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J. et al. (2014). A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum. Mut. 35, 137-146.

Toropova, K., Mladenov, K., and Roberts, A.J. (2017). Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements. Nat. Struct. Mol. Biol. 24, 461-468.

Toropova, K., Zalyte, R., Mukhopadhyay, A.G., Mladenov, M., Carter, A.P., and Roberts, A.J. (2019). Structure of the dynein-2 complex and its assembly with intraflagellar transport trains. Nat. Struct. Mol. Biol. 26, 823-829.

Tsurumi, Y., Hamada, Y., Katoh, Y. and Nakayama, K. (2019). Interactions of the dynein- 2 intermediate chain WDR34 with the light chains are required for ciliary retrograde protein trafficking. Mol. Biol. Cell 30, 658-670.

Vuolo, L., Stevenson, N.L., Heesom, K.J., and Stephens, D.J. (2018). Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function. eLife 7, e39655.

Vuolo, L., Stevenson, N.L., Mukhopadhyay, A.G., Roberts, A.J., and Stephens, D.J. (2020). Cytoplasmic dynein-2 at a glance. J. Cell Sci. 133, jcs240614.

Webb, S., Mukhopadhyay, A.G., and Roberts, A.J. (2020). Intraflagellar transport trains and motors: insights from structure. Sem. Cell Dev. Biol. 107, 82-90.

Ye, F., Nager, A. R. and Nachury, M. V. (2018). BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. J. Cell Biol. 217, 1847-1868.

Zhang, Q., Giacalone, J. C., Searby, C., Stone, E. M., Tucker, B. A. and Sheffield, V. C. (2019). Disruption of RPGR protein interaction network is the common feature of RPGR variations that cause XLRP. Proc. Natl. Acad. Sci. USA 116, 1353- 1360.

Zhang, Q., Li, Y., Zhang, Y., Torres, V. E., Harris, P. C., Ling, K. and Hu, J. (2016). GTP- binding of ARL-3 is activated by ARL-13 as a GEF and stabilized by UNC-119. Sci. Rep. 6, 24534.

Zhang, W., Paige Taylor, S., Ennis, H.A., Forlenza, K.N., Duran, I., Li, B., Ortiz Sanchez, J.A., Nevarez, L., Nickerson, D.A., Bamshad, M., Genomics, U.o.W.C.f.M., Lachman, R.S., Krakow, D., and Cohn, D.H. (2018). Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathy. Hum. Mut. 39, 152-166.

Zhang, X., You, Y., Xie, X., Xu, H., Zhou, H., Lei, Y., Sun, P., Meng, Y., Wang, L., and Lu, Y. (2020). Whole-exome sequencing identified two novel mutations of DYNC2LI1 in fetal skeletal ciliopathy. Mol. Genet. Genomic Med. 8, e1524.

Zhu, X., Wang, J., Li, S., Lechtreck, K., and Pan, J. (2021). IFT54 directly interacts with kinesin-II and IFT dynein to regulate anterograde intraflagellar transport. EMBO J. 40, e105781.

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る