Cholesterol accessibility at the ciliary membrane controls hedgehog signaling

Maia Kinnebrew, Ellen J. Iverson, Bhaven B. Patel, Ganesh V. Pusapati, Jennifer H. Kong, Kristen A. Johnson, Giovanni Luchetti, Kaitlyn M. Eckert, Jeffrey G. McDonald, Douglas F. Covey, Christian Siebold, Arun Radhakrishnan, Rajat Rohatgi

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2 Scopus citations

Abstract

Previously we proposed that transmission of the Hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. Trapping this accessible cholesterol blocks Hedgehog signal transmission across the membrane. Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins.

Original languageEnglish (US)
Article numbere50051
JournaleLife
Volume8
DOIs
StatePublished - Oct 2019

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kinnebrew, M., Iverson, E. J., Patel, B. B., Pusapati, G. V., Kong, J. H., Johnson, K. A., Luchetti, G., Eckert, K. M., McDonald, J. G., Covey, D. F., Siebold, C., Radhakrishnan, A., & Rohatgi, R. (2019). Cholesterol accessibility at the ciliary membrane controls hedgehog signaling. eLife, 8, [e50051]. https://doi.org/10.7554/eLife.50051