Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The roles of evolutionarily conserved functional modules in cilia-related trafficking

Nature Cell Biology volume 15, pages 1387–1397 (2013)Cite this article

Subjects

Abstract

Cilia are present across most eukaryotic phyla and have diverse sensory and motility roles in animal physiology, cell signalling and development. Their biogenesis and maintenance depend on vesicular and intraciliary (intraflagellar) trafficking pathways that share conserved structural and functional modules. The functional units of the interconnected pathways, which include proteins involved in membrane coating as well as small GTPases and their accessory factors, were first experimentally associated with canonical vesicular trafficking. These components are, however, ancient, having been co-opted by the ancestral eukaryote to establish the ciliary organelle, and their study can inform us about ciliary biology in higher organisms.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Functional modules used in membrane trafficking and shaping already established in the last eukaryotic common ancestor (LECA).
Figure 2: Ciliary-vesicle-dependent steps of ciliogenesis, and modular organization and mechanism of the IFT machinery.
Figure 3: Model depicting ciliary cargo trafficking pathways.

Similar content being viewed by others

References

  1. Cavalier-Smith, T. Predation and eukaryote cell origins: a coevolutionary perspective. Int. J. Biochem. Cell Biol. 41, 307–322 (2009).

    CAS  PubMed  Google Scholar 

  2. Bornens, M. The centrosome in cells and organisms. Science 335, 422–426 (2012).

    CAS  PubMed  Google Scholar 

  3. Fisch, C. & Dupuis-Williams, P. Ultrastructure of cilia and flagella – back to the future! Biol. Cell 103, 249–270 (2011).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Carvalho-Santos, Z., Azimzadeh, J., Pereira-Leal, J. B. & Bettencourt-Dias, M. Evolution: Tracing the origins of centrioles, cilia, and flagella. J. Cell Biol. 194, 165–175 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Roy, S. The motile cilium in development and disease: emerging new insights. Bioessays 31, 694–699 (2009).

    CAS  PubMed  Google Scholar 

  7. Shah, A. S., Ben-Shahar, Y., Moninger, T. O., Kline, J. N. & Welsh, M. J. Motile cilia of human airway epithelia are chemosensory. Science 325, 1131–1134 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wong, S. Y. & Reiter, J. F. The primary cilium at the crossroads of mammalian hedgehog signaling. Curr. Top. Dev. Biol. 85, 225–260 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Veland, I. R., Awan, A., Pedersen, L. B., Yoder, B. K. & Christensen, S. T. Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol. 111, 39–53 (2009).

    Google Scholar 

  10. Silverman, M. A. & Leroux, M. R. Intraflagellar transport and the generation of dynamic, structurally and functionally diverse cilia. Trends Cell Biol. 19, 306–316 (2009).

    CAS  PubMed  Google Scholar 

  11. Sung, C. H. & Chuang, J. Z. The cell biology of vision. J. Cell Biol. 190, 953–963 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Christensen, S. T., Clement, C. A., Satir, P. & Pedersen, L. B. Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling. J. Pathol. 226, 172–184 (2012).

    CAS  PubMed  Google Scholar 

  13. Lienkamp, S., Ganner, A. & Walz, G. Inversin, Wnt signaling and primary cilia. Differentiation 83, S49–55 (2012).

    CAS  PubMed  Google Scholar 

  14. Baker, K. & Beales, P. L. Making sense of cilia in disease: the human ciliopathies. Am J Med. Genet. C Semin. Med. Genet. 151C, 281–295 (2009).

    CAS  PubMed  Google Scholar 

  15. Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364, 1533–1543 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Field, M. C. & Dacks, J. B. First and last ancestors: reconstructing evolution of the endomembrane system with ESCRTs, vesicle coat proteins, and nuclear pore complexes. Curr. Opin. Cell Biol. 21, 4–13 (2009).

    CAS  PubMed  Google Scholar 

  17. Field, M. C., Sali, A. & Rout, M. P. Evolution: On a bender — BARs, ESCRTs, COPs, and finally getting your coat. J. Cell Biol. 193, 963–972 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Santarella-Mellwig, R. et al. The compartmentalized bacteria of the planctomycetes–verrucomicrobia–chlamydiae superphylum have membrane coat-like proteins. PLoS Biol. 8, e1000281 (2010).

    PubMed  PubMed Central  Google Scholar 

  19. Hoelz, A., Debler, E. W. & Blobel, G. The structure of the nuclear pore complex. Annu. Rev. Biochem. 80, 613–643 (2011).

    CAS  PubMed  Google Scholar 

  20. Blacque, O. E., Cevik, S. & Kaplan, O. I. Intraflagellar transport: from molecular characterisation to mechanism. Front. Biosci. 13, 2633–2652 (2008).

    CAS  PubMed  Google Scholar 

  21. Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008).

    CAS  PubMed  Google Scholar 

  22. Scholey, J. M. Intraflagellar transport motors in cilia: moving along the cell's antenna. J. Cell Biol. 180, 23–29 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Taschner, M., Bhogaraju, S. & Lorentzen, E. Architecture and function of IFT complex proteins in ciliogenesis. Differentiation 83, S12–22 (2012).

    CAS  PubMed  Google Scholar 

  24. Jekely, G. & Arendt, D. Evolution of intraflagellar transport from coated vesicles and autogenous origin of the eukaryotic cilium. Bioessays 28, 191–198 (2006).

    CAS  PubMed  Google Scholar 

  25. Avidor-Reiss, T. et al. Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell 117, 527–539 (2004).

    CAS  PubMed  Google Scholar 

  26. Blacque, O. E. et al. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 18, 1630–1642 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C. & Mykytyn, K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc. Natl Acad. Sci. USA 105, 4242–4246 (2008).

    CAS  PubMed  Google Scholar 

  28. Jin, H. et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141, 1208–1219 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lechtreck, K. F. et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J. Cell Biol. 187, 1117–1132 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dacks, J. B. & Field, M. C. Evolution of the eukaryotic membrane-trafficking system: origin, tempo and mode. J. Cell Sci. 120, 2977–2985 (2007).

    CAS  PubMed  Google Scholar 

  31. Lim, Y. S., Chua, C. E. & Tang, B. L. Rabs and other small GTPases in ciliary transport. Biol. Cell 103, 209–221 (2011).

    CAS  PubMed  Google Scholar 

  32. Li, Y., Ling, K. & Hu, J. The emerging role of Arf/Arl small GTPases in cilia and ciliopathies. J. Cell Biochem. 113, 2201–2207 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Diekmann, Y. et al. Thousands of rab GTPases for the cell biologist. PLoS Comput. Biol. 7, e1002217 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Peranen, J. Rab8 GTPase as a regulator of cell shape. Cytoskeleton 68, 527–539 (2011).

    PubMed  Google Scholar 

  35. Knodler, A. et al. Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc. Natl. Acad. Sci. USA 107, 6346–6351 (2010).

    CAS  PubMed  Google Scholar 

  36. Nachury, M. V. et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201–1213 (2007).

    CAS  PubMed  Google Scholar 

  37. Omori, Y. et al. Elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nat. Cell Biol. 10, 437–444 (2008).

    CAS  PubMed  Google Scholar 

  38. Westlake, C. J. et al. Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proc. Natl Acad. Sci. USA 108, 2759–2764 (2011).

    CAS  PubMed  Google Scholar 

  39. Schafer, J. C. et al. IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans. J. Cell Sci. 119, 4088–4100 (2006).

    CAS  PubMed  Google Scholar 

  40. Qin, H., Wang, Z., Diener, D. & Rosenbaum, J. Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Curr. Biol. 17, 193–202 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, Z., Fan, Z. C., Williamson, S. M. & Qin, H. Intraflagellar transport (IFT) protein IFT25 is a phosphoprotein component of IFT complex B and physically interacts with IFT27 in Chlamydomonas. PLoS ONE 4, e5384 (2009).

    PubMed  PubMed Central  Google Scholar 

  42. Adhiambo, C., Blisnick, T., Toutirais, G., Delannoy, E. & Bastin, P. A novel function for the atypical small G protein Rab-like 5 in the assembly of the trypanosome flagellum. J. Cell Sci. 122, 834–841 (2009).

    CAS  PubMed  Google Scholar 

  43. Lo, J. C. et al. RAB-like 2 has an essential role in male fertility, sperm intra-flagellar transport, and tail assembly. PLoS Genet. 8, e1002969 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bhogaraju, S., Taschner, M., Morawetz, M., Basquin, C. & Lorentzen, E. Crystal structure of the intraflagellar transport complex 25/27. EMBO J. 30, 1907–1918 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Keady, B. T. et al. IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev. Cell 22, 940–951 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Boehlke, C. et al. Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels. J. Cell Sci. 123, 1460–1467 (2010).

    CAS  PubMed  Google Scholar 

  47. Lumb, J. H. & Field, M. C. Rab23 is a flagellar protein in Trypanosoma brucei. BMC Res. Notes 4, 190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Eggenschwiler, J. T., Bulgakov, O. V., Qin, J., Li, T. & Anderson, K. V. Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev. Biol. 290, 1–12 (2006).

    CAS  PubMed  Google Scholar 

  49. Evans, T. M., Ferguson, C., Wainwright, B. J., Parton, R. G. & Wicking, C. Rab23, a negative regulator of hedgehog signaling, localizes to the plasma membrane and the endocytic pathway. Traffic 4, 869–884 (2003).

    CAS  PubMed  Google Scholar 

  50. Yoshimura, S., Egerer, J., Fuchs, E., Haas, A. K. & Barr, F. A. Functional dissection of Rab GTPases involved in primary cilium formation. J. Cell Biol. 178, 363–369 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Donaldson, J. G. & Jackson, C. L. ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat. Rev. Mol. Cell Biol. 12, 362–375 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fan, Y. et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat. Genet. 36, 989–993 (2004).

    CAS  PubMed  Google Scholar 

  53. Li, Y., Wei, Q., Zhang, Y., Ling, K. & Hu, J. The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis. J. Cell Biol. 189, 1039–1051 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Schmidt, K. N. et al. Cep164 mediates vesicular docking to the mother centriole during early steps of ciliogenesis. J. Cell Biol. 199, 1083–1101 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kaplan, O. I. et al. Endocytosis genes facilitate protein and membrane transport in C. elegans sensory cilia. Curr. Biol. 22, 451–460 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wright, K. J. et al. An ARL3–UNC119–RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev. 25, 2347–2360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schwarz, N., Novoselova, T. V., Wait, R., Hardcastle, A. J. & Cheetham, M. E. The X-linked retinitis pigmentosa protein RP2 facilitates G protein traffic. Hum. Mol. Genet. 21, 863–873 (2012).

    CAS  PubMed  Google Scholar 

  58. Li, J. B. et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117, 541–552 (2004).

    CAS  PubMed  Google Scholar 

  59. Elias, M. & Archibald, J. M. The RJL family of small GTPases is an ancient eukaryotic invention probably functionally associated with the flagellar apparatus. Gene 442, 63–72 (2009).

    CAS  PubMed  Google Scholar 

  60. Dos Santos, G. R. et al. The GTPase TcRjl of the human pathogen Trypanosoma cruzi is involved in the cell growth and differentiation. Biochem. Biophys. Res. Commun. 419, 38–42 (2012).

    PubMed  Google Scholar 

  61. Reiter, J. F., Blacque, O. E. & Leroux, M. R. The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep. 13, 608–618 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Finetti, F. et al. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat. Cell Biol. 11, 1332–1339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sorokin, S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Biol. 15, 363–377 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gorska, M. M., Liang, Q., Karim, Z. & Alam, R. Uncoordinated 119 protein controls trafficking of Lck via the Rab11 endosome and is critical for immunological synapse formation. J. Immunol. 183, 1675–1684 (2009).

    CAS  PubMed  Google Scholar 

  65. Brown, A. C. et al. Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy. PLoS Biol. 9, e1001152 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Dawe, H. R., Farr, H. & Gull, K. Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells. J. Cell Sci. 120, 7–15 (2007).

    CAS  PubMed  Google Scholar 

  67. Johnson, U. G. & Porter, K. R. Fine structure of cell division in Chlamydomonas reinhardi. Basal bodies and microtubules. J. Cell Biol. 38, 403–425 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Sedmak, T. & Wolfrum, U. Intraflagellar transport proteins in ciliogenesis of photoreceptor cells. Biol. Cell 10, 449–466 (2011).

    Google Scholar 

  69. Renaud, F. L. & Swift, H. The development of basal bodies and flagella in Allomyces arbusculus. J. Cell Biol. 23, 339–354 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Moser, J. J., Fritzler, M. J. & Rattner, J. B. Primary ciliogenesis defects are associated with human astrocytoma/glioblastoma cells. BMC Cancer 9, 448 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Hehnly, H., Chen, C. T., Powers, C. M., Liu, H. L. & Doxsey, S. The centrosome regulates the Rab11- dependent recycling endosome pathway at appendages of the mother centriole. Curr. Biol. 22, 1944–1950 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tanos, B. E. et al. Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev. 27, 163–168 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Deane, J. A., Cole, D. G., Seeley, E. S., Diener, D. R. & Rosenbaum, J. L. Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles. Curr. Biol. 11, 1586–1590 (2001).

    CAS  PubMed  Google Scholar 

  74. Sedmak, T. & Wolfrum, U. Intraflagellar transport molecules in ciliary and nonciliary cells of the retina. J. Cell Biol. 189, 171–186 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Williams, C. L. et al. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell Biol. 192, 1023–1041 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Singla, V., Romaguera-Ros, M., Garcia-Verdugo, J. M. & Reiter, J. F. Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev. Cell 18, 410–424 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Goetz, S. C., Liem, K. F. J. & Anderson, K. V. The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell 151, 847–858 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jiang, K. et al. A Proteome-wide screen for mammalian SxIP motif-containing microtubule plus-end tracking proteins. Curr. Biol. 22, 1800–1807 (2012).

    CAS  PubMed  Google Scholar 

  79. Garcia-Gonzalo, F. R. et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat. Genet. 43, 776–784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Garcia-Gonzalo, F. R. & Reiter, J. F. Scoring a backstage pass: Mechanisms of ciliogenesis and ciliary access. J. Cell Biol. 197, 697–709 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kozminski, K. G., Johnson, K. A., Forscher, P. & Rosenbaum, J. L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl Acad. Sci. USA 90, 5519–5523 (1993).

    CAS  PubMed  Google Scholar 

  82. Mizuno, N., Taschner, M., Engel, B. D. & Lorentzen, E. Structural studies of ciliary components. J. Mol. Biol. 422, 163–180 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ou, G. et al. Sensory ciliogenesis in Caenorhabditis elegans: assignment of IFT components into distinct modules based on transport and phenotypic profiles. Mol. Biol. Cell 18, 1554–1569 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hao, L. et al. Intraflagellar transport delivers tubulin isotypes to sensory cilium middle and distal segments. Nat. Cell Biol. 13, 790–798 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Johnson, K. A. & Rosenbaum, J. L. Polarity of flagellar assembly in Chlamydomonas. J. Cell Biol. 119, 1605–1611 (1992).

    CAS  PubMed  Google Scholar 

  86. Hou, Y. et al. Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella. J. Cell Biol. 176, 653–665 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ahmed, N. T., Gao, C., Lucker, B. F., Cole, D. G. & Mitchell, D. R. ODA16 aids axonemal outer row dynein assembly through an interaction with the intraflagellar transport machinery. J. Cell Biol. 183, 313–322 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Qin, H., Diener, D. R., Geimer, S., Cole, D. G. & Rosenbaum, J. L. Intraflagellar transport (IFT) cargo: IFT transports flagellar precursors to the tip and turnover products to the cell body. J. Cell Biol. 164, 255–266 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Pigino, G. et al. Electron-tomographic analysis of intraflagellar transport particle trains in situ. J. Cell Biol. 187, 135–148 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Hao, L., Efimenko, E., Swoboda, P. & Scholey, J. M. The retrograde IFT machinery of C. elegans cilia: two IFT dynein complexes? PLoS ONE 6, e20995 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bhogaraju, S. et al. Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science 341, 1009–1012 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Stephens, R. E. Tubulin and tektin in sea urchin embryonic cilia: pathways of protein incorporation during turnover and regeneration. J. Cell Sci. 107, 683–692 (1994).

    CAS  PubMed  Google Scholar 

  93. Keady, B. T., Le, Y. Z. & Pazour, G. J. IFT20 is required for opsin trafficking and photoreceptor outer segment development. Mol. Biol. Cell 22, 921–930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, Q., Pan, J. & Snell, W. J. Intraflagellar transport particles participate directly in cilium-generated signaling in Chlamydomonas. Cell 125, 549–562 (2006).

    CAS  PubMed  Google Scholar 

  95. Zhang, Q., Seo, S., Bugge, K., Stone, E. M. & Sheffield, V. C. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Hum. Mol. Genet. 21, 1945–1953 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Berbari, N. F., Johnson, A. D., Lewis, J. S., Askwith, C. C. & Mykytyn, K. Identification of Ciliary Localization Sequences within the Third Intracellular Loop of G Protein-Coupled Receptors. Mol. Biol. Cell 19, 1540–1547 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Domire, J. S. et al. Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell Mol. Life Sci. 68, 2951–2960 (2011).

    CAS  PubMed  Google Scholar 

  98. Qin, H. et al. Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr. Biol. 15, 1695–1699 (2005).

    CAS  PubMed  Google Scholar 

  99. Huang, K. et al. Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. J. Cell Biol. 179, 501–514 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Trivedi, D., Colin, E., Louie, C. M. & Williams, D. S. Live-cell imaging evidence for the ciliary transport of rod photoreceptor opsin by heterotrimeric Kinesin-2. J. Neurosci. 32, 10587–10593 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ye, F. et al. Single molecule imaging reveals a major role for diffusion in the exploration of ciliary space by signaling receptors. eLife 2, e00654 (2013).

    PubMed  PubMed Central  Google Scholar 

  102. Bonifacino, J. S. & Traub, L. M. Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu. Rev. Biochem. 72, 395–447 (2003).

    CAS  PubMed  Google Scholar 

  103. Pfeffer, S. R. Transport-vesicle targeting: tethers before SNAREs. Nat. Cell Biol. 1, E17–E22 (1999).

    CAS  PubMed  Google Scholar 

  104. Rodriguez-Boulan, E., Kreitzer, G. & Musch, A. Organization of vesicular trafficking in epithelia. Nat. Rev. Mol. Cell Biol. 6, 233–247 (2005).

    CAS  PubMed  Google Scholar 

  105. Follit, J. A., Li, L., Vucica, Y. & Pazour, G. J. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J. Cell Biol. 188, 21–28 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ward, H. H. et al. A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1. Mol. Biol. Cell 22, 3289–3305 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Geng, L. et al. Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J. Cell Sci. 119, 1383–1395 (2006).

    CAS  PubMed  Google Scholar 

  108. Chuang, J. Z. & Sung, C. H. The cytoplasmic tail of rhodopsin acts as a novel apical sorting signal in polarized MDCK cells. J. Cell Biol. 142, 1245–1256 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Sung, C. H., Makino, C., Baylor, D. & Nathans, J. A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment. J. Neurosci. 14, 5818–5833 (1994).

    CAS  PubMed  Google Scholar 

  110. Sung, C. H., Schneider, B. G., Agarwal, N., Papermaster, D. S. & Nathans, J. Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc. Natl Acad. Sci. USA 88, 8840–8844 (1991).

    CAS  PubMed  Google Scholar 

  111. Tai, A. W., Chuang, J. Z., Bode, C., Wolfrum, U. & Sung, C. H. Rhodopsin's carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97, 877–887 (1999).

    CAS  PubMed  Google Scholar 

  112. Mazelova, J. et al. Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4. EMBO J. 28, 183–192 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Tai, A. W., Chuang, J. Z. & Sung, C. H. Cytoplasmic dynein regulation by subunit heterogeneity and its role in apical transport. J. Cell Biol. 153, 1499–1510 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Follit, J. A., Tuft, R. A., Fogarty, K. E. & Pazour, G. J. The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly. Mol. Biol. Cell 17, 3781–3792 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Abd-El-Barr, M. M. et al. Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet-Biedl syndrome. Int. J. Biochem. Cell Biol. 47, 3394–3407 (2007).

    CAS  Google Scholar 

  116. Kim, J. C. et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat. Genet. 36, 462–470 (2004).

    CAS  PubMed  Google Scholar 

  117. Wang, J., Morita, Y., Mazelova, J. & Deretic, D. The Arf GAP ASAP1 provides a platform to regulate Arf4- and Rab11–Rab8-mediated ciliary receptor targeting. EMBO J. 31, 4057–4071 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Chiba, S., Amagai, Y., Homma, Y., Fukuda, M. & Mizuno, K. NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15. EMBO J. 32, 874–885 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Weisz, O. A. & Rodriguez-Boulan, E. Apical trafficking in epithelial cells: signals, clusters and motors. J. Cell Sci. 122, 4253–4266 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Maxfield, F. R. & McGraw, T. E. Endocytic recycling. Nat. Rev. Mol. Cell Biol. 5, 121–132 (2004).

    CAS  PubMed  Google Scholar 

  121. Apodaca, G., Katz, L. A. & Mostov, K. E. Receptor-mediated transcytosis of IgA in MDCK cells is via apical recycling endosomes. J. Cell Biol. 125, 67–86 (1994).

    CAS  PubMed  Google Scholar 

  122. Zuo, X., Guo, W. & Lipschutz, J. H. The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol. Biol. Cell 20, 2522–2529 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Prigent, M. et al. ARF6 controls post-endocytic recycling through its downstream exocyst complex effector. J Cell Biol 163, 1111–1121 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Hoffmeister, H. et al. Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. J. Cell Biol. 192, 631–645 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim, J. et al. Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 464, 1048–1051 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Kaplan, O. I. et al. The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport. J. Cell Sci. 123, 3966–3977 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bryant, D. M. et al. A molecular network for de novo generation of the apical surface and lumen. Nat. Cell Biol. 12, 1035–1045 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Milenkovic, L., Scott, M. P. & Rohatgi, R. Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium. J. Cell Biol. 187, 365–374 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Schwarz, N., Hardcastle, A. J. & Cheetham, M. E. Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins. Vision Res. 75, 2–4 (2012).

    CAS  PubMed  Google Scholar 

  130. Pretorius, P. R. et al. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS Genet. 6, e1000884 (2010).

    PubMed  PubMed Central  Google Scholar 

  131. Wu, V. M., Chen, S. C., Arkin, M. R. & Reiter, J. F. Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis. Proc. Natl. Acad. Sci. USA 109, 13644–13449 (2012).

    CAS  PubMed  Google Scholar 

  132. Wickstead, B. & Gull, K. A “holistic” kinesin phylogeny reveals new kinesin families and predicts protein functions. Mol. Biol. Cell 17, 1734–1743 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Wickstead, B. & Gull, K. Dyneins across eukaryotes: a comparative genomic analysis. Traffic 8, 1708–1721 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Briggs, L. J., Davidge, J. A., Wickstead, B., Ginger, M. L. & Gull, K. More than one way to build a flagellum: comparative genomics of parasitic protozoa. Curr. Biol. 14, R611–R612 (2004).

    CAS  PubMed  Google Scholar 

  135. Mukhopadhyay, S. et al. 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 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Malicki, J. Who drives the ciliary highway? Bioarchitecture 2, 111–117 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. Blacque, O. E. & Leroux, M. R. Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport. Cell. Mol. Life Sci. 63, 2145–2161 (2006).

    CAS  PubMed  Google Scholar 

  138. Zaghloul, N. A. & Katsanis, N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J. Clin. Invest. 119, 428–437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Seo, S. et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc. Natl Acad. Sci. USA 107, 1488–1493 (2010).

    CAS  PubMed  Google Scholar 

  140. Chiang, A. P. et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc. Natl Acad. Sci. USA 103, 6287–6292 (2006).

    CAS  PubMed  Google Scholar 

  141. Leitch, C. C. et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat. Genet. 40, 443–448 (2008).

    CAS  PubMed  Google Scholar 

  142. Schaefer, E. et al. Mutations in SDCCAG8/NPHP10 cause Bardet-Biedl syndrome and are associated with penetrant renal disease and absent polydactyly. Mol. Syndromol. 1, 273–281 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim, S. K. et al. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329, 1337–1340 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Loktev, A. V. et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev. Cell 15, 854–865 (2008).

    CAS  PubMed  Google Scholar 

  145. Ou, G., Blacque, O. E., Snow, J. J., Leroux, M. R. & Scholey, J. M. Functional coordination of intraflagellar transport motors. Nature 436, 583–587 (2005).

    CAS  PubMed  Google Scholar 

  146. Wei, Q. et al. The BBSome controls IFT assembly and turnaround in cilia. Nat. Cell Biol. 14, 950–957 (2012).

    PubMed  PubMed Central  Google Scholar 

  147. Seo, S. et al. A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet. 7, e1002358 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Marion, V. et al. Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly. J. Med. Genet. 49, 317–321 (2012).

    PubMed  Google Scholar 

  149. Johnson, J. L. & Leroux, M. R. cAMP and cGMP signaling: sensory systems with prokaryotic roots adopted by eukaryotic cilia. Trends Cell Biol. 20, 435–444 (2010).

    CAS  PubMed  Google Scholar 

  150. Mok, C. A. et al. Mutations in a guanylate cyclase GCY-35/GCY-36 modify Bardet-Biedl syndrome-associated phenotypes in Caenorhabditis elegans. PLoS Genet. 7, e1002335 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The field of cilium trafficking has grown tremendously in the last few years and the authors apologize for not covering all relevant studies due to space restrictions. M.R.L. acknowledges funding from the Canadian Institutes of Health Research (CIHR; grant MOP-123527) and a senior scholar award from Michael Smith Foundation for Health Research (MSFHR). C.H.S. is funded by NIH-EY11307, NIH-EY016805, Research To Prevent Blindness, and Starr Stem Cell Foundation.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Ching-Hwa Sung is at the Margaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA,

    Ching-Hwa Sung

  2. Michel R. Leroux is in the Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada,

    Michel R. Leroux

Authors
  1. Ching-Hwa Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel R. Leroux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel R. Leroux.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sung, CH., Leroux, M. The roles of evolutionarily conserved functional modules in cilia-related trafficking. Nat Cell Biol 15, 1387–1397 (2013). https://doi.org/10.1038/ncb2888

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2888

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing