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 Beachy; Jeremy F Reiter

doi:10.1016/j.molcel.2018.08.034

Cilia-Associated Oxysterols Activate Smoothened

Mol Cell. 2018 Oct 18;72(2):316-327.e5. doi: 10.1016/j.molcel.2018.08.034.

Authors

David R Raleigh¹, Navdar Sever², Pervinder K Choksi³, Monika Abedin Sigg⁴, Kelly M Hines⁵, Bonne M Thompson⁶, Daniel Elnatan⁴, Priyadarshini Jaishankar⁷, Paola Bisignano⁸, Francesc R Garcia-Gonzalo⁴, Alexis Leigh Krup³, Markus Eberl⁹, Eamon F X Byrne¹⁰, Christian Siebold¹⁰, Sunny Y Wong⁹, Adam R Renslo⁷, Michael Grabe⁸, Jeffrey G McDonald¹¹, Libin Xu⁵, Philip A Beachy¹², Jeremy F Reiter¹³

Affiliations

¹ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
² Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
⁶ Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹¹ Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹² Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Urology and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: jeremy.reiter@ucsf.edu.

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.

Keywords: CBP; HSD11β2; Hedgehog; Smoothened; cilia; lipid; medulloblastoma; oxysterol; primary cilium; sterol.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cilia / drug effects*
Cilia / metabolism*
HEK293 Cells
Hedgehog Proteins / metabolism
Humans
Mice
NIH 3T3 Cells
Oxysterols / pharmacology*
Signal Transduction / drug effects

Substances

Hedgehog Proteins
Oxysterols

Abstract

Publication types

MeSH terms

Substances

Grants and funding