Cilia-Associated Oxysterols Activate Smoothened

David R. Raleigh, Navdar Sever, Pervinder K. Choksi, Monika Abedin Sigg, Kelly M. Hines, Bonne M. Thompson, Daniel Elnatan, Priyadarshini Jaishankar, Paola Bisignano, Francesc R. Garcia-Gonzalo, Alexis Leigh Krup, Markus Eberl, Eamon F.X. Byrne, Christian Siebold, Sunny Y. Wong, Adam R. Renslo, Michael Grabe, Jeffrey G. McDonald, Libin Xu, Philip A. BeachyJeremy F. Reiter

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associated oxysterols that promote Smoothened accumulation in cilia and activate the Hedgehog pathway. Our data reveal that cilia-associated oxysterols bind to two distinct Smoothened domains to modulate Smoothened accumulation in cilia and tune the intensity of Hedgehog pathway activation. We find that the oxysterol synthase HSD11β2 participates in the production of Smoothened-activating oxysterols and promotes Hedgehog pathway activity. Inhibiting oxysterol biosynthesis impedes oncogenic Hedgehog pathway activation and attenuates the growth of Hedgehog pathway-associated medulloblastoma, suggesting that targeted inhibition of Smoothened-activating oxysterol production may be therapeutically useful for patients with Hedgehog-associated cancers. How Smoothened localizes to primary cilia and is activated is poorly understood. Raleigh et al. find that cilia contain oxysterol lipids that bind to Smoothened and activate the Hedgehog pathway. Moreover, they identify an enzyme involved in cilia-associated oxysterol biosynthesis that is enriched in Hedgehog pathway-associated medulloblastoma and that blocking this enzyme using a compound in black licorice inhibits tumor growth.

Original languageEnglish (US)
Pages (from-to)316-327.e5
JournalMolecular cell
Volume72
Issue number2
DOIs
StatePublished - Oct 18 2018

Keywords

  • CBP
  • HSD11β2
  • Hedgehog
  • Smoothened
  • cilia
  • lipid
  • medulloblastoma
  • oxysterol
  • primary cilium
  • sterol

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Raleigh, D. R., Sever, N., Choksi, P. K., Sigg, M. A., Hines, K. M., Thompson, B. M., Elnatan, D., Jaishankar, P., Bisignano, P., Garcia-Gonzalo, F. R., Krup, A. L., Eberl, M., Byrne, E. F. X., Siebold, C., Wong, S. Y., Renslo, A. R., Grabe, M., McDonald, J. G., Xu, L., ... Reiter, J. F. (2018). Cilia-Associated Oxysterols Activate Smoothened. Molecular cell, 72(2), 316-327.e5. https://doi.org/10.1016/j.molcel.2018.08.034