Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.
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4 January 2021
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December 07 2020
Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway
Sarah Findakly,
Sarah Findakly
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Vikas Daggubati,
Vikas Daggubati
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Galo Garcia, III,
Galo Garcia, III
3
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
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Sydney A. LaStella,
Sydney A. LaStella
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Abrar Choudhury,
Abrar Choudhury
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Cecilia Tran,
Cecilia Tran
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
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Amy Li,
Amy Li
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
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Pakteema Tong,
Pakteema Tong
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
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Jason Q. Garcia,
Jason Q. Garcia
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Natasha Puri,
Natasha Puri
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
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Jeremy F. Reiter,
Jeremy F. Reiter
3
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
5
Chan Zuckerberg Biohub, San Francisco, CA
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Libin Xu,
Libin Xu
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
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David R. Raleigh
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Correspondence to David R. Raleigh: david.raleigh@ucsf.edu
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Sarah Findakly
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Vikas Daggubati
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Galo Garcia, III
3
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
Sydney A. LaStella
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Abrar Choudhury
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Cecilia Tran
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
Amy Li
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
Pakteema Tong
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
Jason Q. Garcia
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Natasha Puri
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Jeremy F. Reiter
3
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
5
Chan Zuckerberg Biohub, San Francisco, CA
4
Department of Medicinal Chemistry, University of Washington, Seattle, WA
David R. Raleigh
1
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Correspondence to David R. Raleigh: david.raleigh@ucsf.edu
Received:
February 05 2020
Revision Received:
August 12 2020
Accepted:
October 28 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
National Institutes of Health
(GM105755)
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (1): e202002026.
Article history
Received:
February 05 2020
Revision Received:
August 12 2020
Accepted:
October 28 2020
Citation
Sarah Findakly, Vikas Daggubati, Galo Garcia, Sydney A. LaStella, Abrar Choudhury, Cecilia Tran, Amy Li, Pakteema Tong, Jason Q. Garcia, Natasha Puri, Jeremy F. Reiter, Libin Xu, David R. Raleigh; Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway. J Cell Biol 4 January 2021; 220 (1): e202002026. doi: https://doi.org/10.1083/jcb.202002026
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