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.

  • Article
  • Published:

The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression

Nature Genetics volume 36, pages 462–470 (2004)Cite this article

Abstract

BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150glued subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: BBS4 interacts with PCM1.
Figure 2: BBS4 is a pericentriolar protein associated with centrosomes and basal bodies.
Figure 3: Localization of BBS4 to centrosomal satellites depends on both N- and C-terminal TPRs.
Figure 4: Incorrect localization of BBS4 affects the behavior of PCM1.
Figure 5: BBS4 dependence on, and interaction with, the dynein complex.
Figure 6: Loss of BBS4 function.
Figure 7: Histological localization of BBS4 and PCM1.
Figure 8: Model of BBS4 (dys)function.

Similar content being viewed by others

References

  1. Zimmerman, W., Sparks, C.A. & Doxsey, S.J. Amorphous no longer: the centrosome comes into focus. Curr. Opin. Cell Biol. 11, 122–128 (1999).

    Article  CAS  Google Scholar 

  2. Zimmerman, W. & Doxsey, S.J. Construction of centrosomes and spindle poles by molecular motor-driven assembly of protein particles. Traffic 1, 927–934 (2000).

    CAS  Google Scholar 

  3. Ou, Y.Y., Zhang, M., Chi, S., Matyas, J.R. & Rattner, J.B. Higher order structure of the PCM adjacent to the centriole. Cell Motil. Cytoskeleton 55, 125–133 (2003).

    Article  Google Scholar 

  4. Kubo, A., Sasaki, H., Yuba-Kubo, A., Tsukita, S. & Shiina, N. Centriolar satellites: Molecular characterization, ATP-dependent movement toward centrioles and possible involvement in ciliogenesis. J. Cell Biol. 147, 969–979 (1999).

    Article  CAS  Google Scholar 

  5. Rattner, J.B. Ultrastructure of centrosome domains and identification of their protein components. in In The Centrosome (ed. Kalnins, V.I.) 45–69 (Academic, San Diego, 1992).

    Chapter  Google Scholar 

  6. Bobinnec, Y. et al. Centriole disassembly in vivo and its effect on centrosome structure and function in vertebrate cells. J. Cell Biol. 143, 1575–1589 (1998).

    Article  CAS  Google Scholar 

  7. Beisson, J. & Wright, M. Basal body/centriole assembly and continuity. Curr. Opin. Cell Biol. 15, 96–104 (2003).

    Article  CAS  Google Scholar 

  8. Balczon, R., Bao, L. & Zimmer, W.E. PCM-1, A 228-kD centrosome autoantigen with a distinct cell cycle distribution. J. Cell Biol. 124, 783–793 (1994).

    Article  CAS  Google Scholar 

  9. Dammermann, A. & Merdes, A. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. J. Cell Biol. 159, 255–266 (2002).

    Article  CAS  Google Scholar 

  10. Beales, P.L., Elcioglu, N., Woolf, A.S., Parker, D. & Flinter, F.A. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet. 36, 437–446 (1999).

    CAS  Google Scholar 

  11. Katsanis, N. et al. Triallelic inheritance in Bardet-Biedl syndrome, a mendelian recessive disorder. Science 293, 2256–2259 (2001).

    Article  CAS  Google Scholar 

  12. Badano, J.L. et al. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am. J. Hum. Genet. 72, 650–658 (2003).

    Article  CAS  Google Scholar 

  13. Mykytyn, K. et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat. Genet. 31, 435–438 (2002).

    Article  CAS  Google Scholar 

  14. Mykytyn, K. et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat. Genet. 28, 188–191 (2001).

    Article  CAS  Google Scholar 

  15. Nishimura, D.Y. et al. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum. Mol. Genet. 10, 865–874 (2001).

    Article  CAS  Google Scholar 

  16. Katsanis, N. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat. Genet. 26, 67–70 (2000).

    Article  CAS  Google Scholar 

  17. Slavotinek, A.M. et al. Mutations in MKKS cause Bardet-Biedl syndrome. Nat. Genet. 26, 15–16 (2000).

    Article  CAS  Google Scholar 

  18. Ansley, S.J. et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425, 628–633 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Schultz, J., Copley, R.R., Doerks, T., Ponting, C.P. & Bork, P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 28, 231–234 (2000).

    Article  CAS  Google Scholar 

  21. Blatch, G.L. & Lassle, M. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21, 932–939 (1999).

    Article  CAS  Google Scholar 

  22. Moudjou, M., Bordes, N., Paintrand, M. & Bornens, M. gamma-Tubulin in mammalian cells: the centrosomal and the cytosolic forms. J. Cell Sci. 109, 875–887 (1996).

    CAS  Google Scholar 

  23. Dictenberg, J.B. et al. Pericentrin and gamma-tubulin form a protein complex and are organized into a novel lattice at the centrosome. J. Cell Biol. 141, 163–174 (1998).

    Article  CAS  Google Scholar 

  24. Vaughan, K.T. & Vallee, R.B. Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued . J. Cell Biol. 131, 1507–1516 (1995).

    Article  CAS  Google Scholar 

  25. Valle, R.D. The molecular motor toolbox for intracellular transport. Cell 112, 467–480 (2003).

    Article  Google Scholar 

  26. Waterman-Storer, C.M., Karki, S. & Holzhbaur, E.L. The p150Glued component of the dynactin complex binds to both microtubules and the actin-related protein centractin (Arp-1). Proc. Natl. Acad. Sci. USA 92, 1634–1638 (1995).

    Article  CAS  Google Scholar 

  27. Balczon, R., Varden, C.E. & Schroer, T.A. Role for microtubules in centrosome doubling in Chinese hamster ovary cells. Cell Motil. Cytoskeleton 42, 60–72 (1999).

    Article  CAS  Google Scholar 

  28. Young, A., Dictenberg, J.B., Purohit, A., Tuft, R. & Doxsey, S.J. Cytoplasmic dynein-mediated assembly of pericentrin and gamma tubulin onto centrosomes. Mol. Biol. Cell 11, 2047–2056 (2000).

    Article  CAS  Google Scholar 

  29. Brummelkamp, T.R., Bernards, R., Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Beh and S. Huston for their critical evaluation of this manuscript and P. Scambler for discussions. This study was supported in part by a National Institute of Child Health and Development, National Institutes of Health grant and the March of Dimes (N.K.); National Cancer Institute of Canada (Terry Fox Run) and Heart and Stroke Foundation of BC and Yukon (M.R.L.); the National Kidney Research Fund (B.E.H.); and the Birth Defects Foundation and the Wellcome Trust (P.L.B.). P.L.B. is a Wellcome Trust Senior Research Fellow. J.C.K. and M.A.E. hold scholarships from the Michael Smith Foundation for Health Research and Heart and Stroke Foundation of Canada, respectively, and M.R.L. is the recipient of scholar awards from the Canadian Institutes of Health Research and Michael Smith Foundation for Health Research.

Author information

Author notes

  1. Jun Chul Kim, Jose L Badano and Sonja Sibold: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Dr., Burnaby, V5A 1S6, BC, Canada

    Jun Chul Kim, Muneer A Esmail & Michel R Leroux

  2. Institute of Genetic Medicine, Johns Hopkins University, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Jose L Badano, Carmen C Leitch, Stephen J Ansley & Nicholas Katsanis

  3. Molecular Medicine Unit, Institute of Child Health, University College London, London, WC1N 1EH, UK

    Sonja Sibold, Josephine Hill, Bethan E Hoskins, Alison J Ross & Philip L Beales

  4. Department of Electron Microscopy, Institute of Neurology, Queens Square, London, UK

    Kerrie Venner

  5. Wilmer Eye Institute, Johns Hopkins University, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Nicholas Katsanis

Authors
  1. Jun Chul Kim
    View author publications

    Search author on:PubMed Google Scholar

  2. Jose L Badano
    View author publications

    Search author on:PubMed Google Scholar

  3. Sonja Sibold
    View author publications

    Search author on:PubMed Google Scholar

  4. Muneer A Esmail
    View author publications

    Search author on:PubMed Google Scholar

  5. Josephine Hill
    View author publications

    Search author on:PubMed Google Scholar

  6. Bethan E Hoskins
    View author publications

    Search author on:PubMed Google Scholar

  7. Carmen C Leitch
    View author publications

    Search author on:PubMed Google Scholar

  8. Kerrie Venner
    View author publications

    Search author on:PubMed Google Scholar

  9. Stephen J Ansley
    View author publications

    Search author on:PubMed Google Scholar

  10. Alison J Ross
    View author publications

    Search author on:PubMed Google Scholar

  11. Michel R Leroux
    View author publications

    Search author on:PubMed Google Scholar

  12. Nicholas Katsanis
    View author publications

    Search author on:PubMed Google Scholar

  13. Philip L Beales
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Michel R Leroux or Nicholas Katsanis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Badano, J., Sibold, S. 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). https://doi.org/10.1038/ng1352

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/ng1352

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