title: Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols.
abstract: Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith-Lemli-Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-β-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3β,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith-Lemli-Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305; Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Navdar
authors.initials: N
authors.lastname: Sever
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305; Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Randall K
authors.initials: RK
authors.lastname: Mann
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235;
authors.forename: Libin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: William J
authors.initials: WJ
authors.lastname: Snell
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Carmen I
authors.initials: CI
authors.lastname: Hernandez-Lara
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235;
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305; Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; pbeachy@stanford.edu.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000818:Animals; D016825:Chlamydomonas reinhardtii / Q000737:chemistry; D003684:Dehydrocholesterols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005407:Flagella / Q000737:chemistry; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015398:Signal Transduction; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor / Q000235:genetics / Q000378:metabolism*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D003684:Dehydrocholesterols; D053823:Hedgehog Proteins; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C016705:7-dehydrocholesterol; C000541:cyclopamine
keywords: DHCEO; Hedgehog signaling; SLOS; Smoothened; cyclodextrin