Cilia-Associated Oxysterols Activate Smoothened

• Published in: Molecular cell Vol. 72; no. 2; pp. 316 - 327.e5
• Main Authors: Raleigh, David R., Sever, Navdar, Choksi, Pervinder K., Sigg, Monika Abedin, Hines, Kelly M., Thompson, Bonne M., Elnatan, Daniel, Jaishankar, Priyadarshini, Bisignano, Paola, Garcia-Gonzalo, Francesc R., Krup, Alexis Leigh, Eberl, Markus, Byrne, Eamon F.X., Siebold, Christian, Wong, Sunny Y., Renslo, Adam R., Grabe, Michael, McDonald, Jeffrey G., Xu, Libin, Beachy, Philip A., Reiter, Jeremy F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2018
• Subjects: Animals; CBP; Cell Line; cilia; Cilia - drug effects; Cilia - metabolism; Hedgehog; Hedgehog Proteins - metabolism; HEK293 Cells; HSD11β2; Humans; lipid; medulloblastoma; Mice; NIH 3T3 Cells; oxysterol; Oxysterols - pharmacology; primary cilium; Signal Transduction - drug effects; Smoothened; sterol; CBP; HSD11β2; oxysterol; Hedgehog; primary cilium; Smoothened; sterol; medulloblastoma; cilia; lipid
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.08.034

Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associated oxysterols that promote Smoothened accumulation in cilia and activate the Hedgehog pathway. Our data reveal that cilia-associated oxysterols bind to two distinct Smoothened domains to modulate Smoothened accumulation in cilia and tune the intensity of Hedgehog pathway activation. We find that the oxysterol synthase HSD11β2 participates in the production of Smoothened-activating oxysterols and promotes Hedgehog pathway activity. Inhibiting oxysterol biosynthesis impedes oncogenic Hedgehog pathway activation and attenuates the growth of Hedgehog pathway-associated medulloblastoma, suggesting that targeted inhibition of Smoothened-activating oxysterol production may be therapeutically useful for patients with Hedgehog-associated cancers. [Display omitted] •Primary cilia from diverse organisms and tissues contain oxysterol lipids•Cilia-associated oxysterols bind and activate Smoothened through multiple domains•The oxysterol synthase HSD11β2 generates Smoothened-activating oxysterols•HSD11β2 is enriched in medulloblastoma, and blocking HSD11β2 inhibits cancer growth How Smoothened localizes to primary cilia and is activated is poorly understood. Raleigh et al. find that cilia contain oxysterol lipids that bind to Smoothened and activate the Hedgehog pathway. Moreover, they identify an enzyme involved in cilia-associated oxysterol biosynthesis that is enriched in Hedgehog pathway-associated medulloblastoma and that blocking this enzyme using a compound in black licorice inhibits tumor growth.