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Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway
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 un...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721912/ https://www.ncbi.nlm.nih.gov/pubmed/33284321 http://dx.doi.org/10.1083/jcb.202002026 |
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author | Findakly, Sarah Daggubati, Vikas Garcia, Galo LaStella, Sydney A. Choudhury, Abrar Tran, Cecilia Li, Amy Tong, Pakteema Garcia, Jason Q. Puri, Natasha Reiter, Jeremy F. Xu, Libin Raleigh, David R. |
author_facet | Findakly, Sarah Daggubati, Vikas Garcia, Galo LaStella, Sydney A. Choudhury, Abrar Tran, Cecilia Li, Amy Tong, Pakteema Garcia, Jason Q. Puri, Natasha Reiter, Jeremy F. Xu, Libin Raleigh, David R. |
author_sort | Findakly, Sarah |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7721912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77219122021-07-04 Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway Findakly, Sarah Daggubati, Vikas Garcia, Galo LaStella, Sydney A. Choudhury, Abrar Tran, Cecilia Li, Amy Tong, Pakteema Garcia, Jason Q. Puri, Natasha Reiter, Jeremy F. Xu, Libin Raleigh, David R. J Cell Biol Report 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. Rockefeller University Press 2020-12-07 /pmc/articles/PMC7721912/ /pubmed/33284321 http://dx.doi.org/10.1083/jcb.202002026 Text en This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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/). |
spellingShingle | Report Findakly, Sarah Daggubati, Vikas Garcia, Galo LaStella, Sydney A. Choudhury, Abrar Tran, Cecilia Li, Amy Tong, Pakteema Garcia, Jason Q. Puri, Natasha Reiter, Jeremy F. Xu, Libin Raleigh, David R. Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title | Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title_full | Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title_fullStr | Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title_full_unstemmed | Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title_short | Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway |
title_sort | sterol and oxysterol synthases near the ciliary base activate the hedgehog pathway |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721912/ https://www.ncbi.nlm.nih.gov/pubmed/33284321 http://dx.doi.org/10.1083/jcb.202002026 |
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