Endogenous B-ring oxysterols inhibit the hedgehog component smoothened in a manner distinct from cyclopamine or side-chain oxysterols

Navdar Sever, Randall K. Mann, Libin Xu, William J. Snell, Carmen I. Hernandez-Lara, Ned A. Porter, Philip A. Beachy

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5904-5909
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number21
DOIs
StatePublished - May 24 2016

Keywords

  • Cyclodextrin
  • DHCEO
  • Hedgehog signaling
  • SLOS
  • Smoothened

ASJC Scopus subject areas

  • General

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