Endogenous B-ring Oxysterols Inhibit the Hedgehog Component Smoothened in a Manner Distinct from Cyclopamine or Side-chain Oxysterols

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 May 11

PMID 27162362

Citations 32

Authors

Navdar Sever

Randall K Mann

Libin Xu

William J Snell

Carmen I Hernandez-Lara

Ned A Porter

Philip A Beachy

Affiliations

Soon will be listed here.

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.

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