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

Cilia-Associated Oxysterols Activate Smoothened.

Author information

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

PMID:
30340023
PMCID:
PMC6503851
DOI:
10.1016/j.molcel.2018.08.034
[Indexed for MEDLINE]
Free PMC Article

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