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The BBSome controls IFT assembly and turnaround in cilia

Nature Cell Biology volume 14, pages 950–957 (2012)Cite this article

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Abstract

The bidirectional movement of intraflagellar transport (IFT) particles, which are composed of motors, IFT-A and IFT-B subcomplexes, and cargoes, is required for the biogenesis and signalling of cilia1,2. A successful IFT cycle depends on the proper assembly of the massive IFT particle at the ciliary base and its turnaround from anterograde to retrograde transport at the ciliary tip. However, how IFT assembly and turnaround are regulated in vivo remains elusive. From a whole-genome mutagenesis screen in Caenorhabditis elegans, we identified two hypomorphic mutations in dyf-2 and bbs-1 as the only mutants showing normal anterograde IFT transport but defective IFT turnaround at the ciliary tip. Further analyses revealed that the BBSome (refs 3, 4), a group of conserved proteins affected in human Bardet–Biedl syndrome5 (BBS), assembles IFT complexes at the ciliary base, then binds to the anterograde IFT particle in a DYF-2- (an orthologue of human WDR19) and BBS-1-dependent manner, and lastly reaches the ciliary tip to regulate proper IFT recycling. Our results identify the BBSome as the key player regulating IFT assembly and turnaround in cilia.

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Figure 1: The G361R mutation in the conserved WD40 domain of the DYF-2 protein abolishes retrograde IFT transport of OSM-6.
Figure 2: dyf-2(jhu616) animals show compromised IFT turnaround at the ciliary tip.
Figure 3: Lack of a functional BBSome in dyf-2(jhu616) cilia.
Figure 4: The BBSome and DYF-2 coordinate IFT assembly and turnaround at the ciliary tip.
Figure 5: Model for the role of the BBSome in IFT assembly and turnaround.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Scholey, J. M. & Anderson, K. V. Intraflagellar transport and cilium-based signaling. Cell 125, 439–442 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Pedersen, L. B., Geimer, S. & Rosenbaum, J. L. Dissecting the molecular mechanisms of intraflagellar transport in Chlamydomonas. Curr. Biol. 16, 450–459 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Hedgecock, E. M., Culotti, J. G., Thomson, J. N. & Perkins, L. A. Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Dev. Biol. 111, 158–170 (1985).

    Article  CAS  PubMed  Google Scholar 

  9. Efimenko, E. et al. Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia. Mol. Biol. Cell 17, 4801–4811 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Snow, J. J. et al. Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C. elegans neurons. Nat. Cell Biol. 6, 1109–1113 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Hu, C. D., Chinenov, Y. & Kerppola, T. K. Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol. Cell 9, 789–798 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Cole, D. G. et al. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J. Cell Biol. 141, 993–1008 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iomini, C., Li, L., Esparza, J. M. & Dutcher, S. K. Retrograde intraflagellar transport mutants identify complex A proteins with multiple genetic interactions in Chlamydomonas reinhardtii. Genetics 183, 885–896 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Piperno, G. et al. Distinct mutants of retrograde intraflagellar transport (IFT) share similar morphological and molecular defects. J. Cell Biol. 143, 1591–1601 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iomini, C., Babaev-Khaimov, V., Sassaroli, M. & Piperno, G. Protein particles in Chlamydomonas flagella undergo a transport cycle consisting of four phases. J. Cell Biol. 153, 13–24 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liem, K. F. Jr et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J. Cell Biol. 197, 789–800 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pazour, G. J., Wilkerson, C. G. & Witman, G. B. A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J. Cell Biol. 141, 979–992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Signor, D. et al. Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans. J. Cell Biol. 147, 519–530 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schafer, J. C., Haycraft, C. J., Thomas, J. H., Yoder, B. K. & Swoboda, P. XBX-1 encodes a dynein light intermediate chain required for retrograde intraflagellar transport and cilia assembly in Caenorhabditis elegans. Mol. Biol. Cell 14, 2057–2070 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fliegauf, M., Benzing, T. & Omran, H. When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol. 8, 880–893 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tayeh, M. K. et al. Genetic interaction between Bardet–Biedl syndrome genes and implications for limb patterning. Human Mol. Genet. 17, 1956–1967 (2008).

    Article  CAS  Google Scholar 

  25. Yen, H. J. et al. Bardet–Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer’s vesicle cilia function. Human Mol. Genet. 15, 667–677 (2006).

    Article  CAS  Google Scholar 

  26. Fath, M. A. et al. Mkks-null mice have a phenotype resembling Bardet–Biedl syndrome. Human Mol. Genet. 14, 1109–1118 (2005).

    Article  CAS  Google Scholar 

  27. Mykytyn, K. et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc. Natl Acad. Sci. USA 101, 8664–8669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nishimura, D. Y. et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc. Natl Acad. Sci. USA 101, 16588–16593 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shah, A. S. et al. Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia. Proc. Natl Acad. Sci. USA 105, 3380–3385 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Davis, R. E. et al. A knockin mouse model of the Bardet–Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc. Natl Acad. Sci. USA 104, 19422–19427 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pan, X. et al. Mechanism of transport of IFT particles in C. elegans cilia by the concerted action of kinesin-II and OSM-3 motors. J. Cell Biol. 174, 1035–1045 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tran, P. V. et al. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat. Genet. 40, 403–410 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. May, S.R. et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev. Biol. 287, 378–389 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Huangfu, D. & Anderson, K. V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl Acad. Sci. USA 102, 11325–11330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gerdes, J. M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat. Genet. 39, 1350–1360 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Davis, M.W. et al. Rapid single nucleotide polymorphism mapping in C. elegans. BMC Genom. 6, 118 (2005).

    Article  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shyu, Y. J. et al. Visualization of protein interactions in living Caenorhabditis elegans using bimolecular fluorescence complementation analysis. Nat. Protocol. 3, 588–596 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Caenorhabditis Genetics Center, the Japanese Bioresource Project, J. Scholey (University of California, Davis, USA), M. Leroux (Simon Fraser University, Canada) and M. Barr (Rutgers University, USA) for strains; and A. Fire (Stanford University, USA) for GFP vectors. J.H. and co-workers were supported by the National Institutes of Health research grant 1R01DK090038 and P30 center grant P30DK90728, a Pilot and Feasibility Award from the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567) and the PKD Foundation Young Investigator Award 04YI09a. J.H. was also supported by a FULK Career Development Award, a Zell PKD Research Award and the Upjohn PKD Research Fund. K.L. was supported by the National Cancer Institute (NCI; 1R01CA149039-01A1), Susan G. Komen for the Cure (KG100902) and the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK90728).

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  1. Qing Wei and Yuxia Zhang: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Rochester, Minnesota 55905, USA

    Qing Wei, Yuxia Zhang, Yujie Li, Qing Zhang & Jinghua Hu

  2. Mayo Translational PKD Center, Rochester, Minnesota 55905, USA

    Kun Ling & Jinghua Hu

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA

    Kun Ling & Jinghua Hu

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Contributions

J.H. conceived the initial concept for the screen. J.H., Q.W., Y.L. and Y.Z. performed the screening and mapped the mutants. Q.W. and Y.Z. generated transgenic animals and performed image analysis with the support of Q.Z. Y.Z. carried out all microinjections. Q.W. and K.L. carried out biochemical assays with the support of Y.Z. K.L. and J.H. wrote the manuscript with contributions from Q.W., Y.Z., Y.L. and Q.Z.

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Correspondence to Jinghua Hu.

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Wei, Q., Zhang, Y., Li, Y. et al. The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol 14, 950–957 (2012). https://doi.org/10.1038/ncb2560

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