Cholesterol access in cellular membranes controls Hedgehog signaling

Arun Radhakrishnan, Rajat Rohatgi, Christian Siebold

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations

Abstract

The Hedgehog (Hh) signaling pathway coordinates cell–cell communication in development and regeneration. Defects in this pathway underlie diseases ranging from birth defects to cancer. Hh signals are transmitted across the plasma membrane by two proteins, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1, a transporter-like tumor-suppressor protein, binds to Hh ligands, but SMO, a G-protein-coupled-receptor family oncoprotein, transmits the Hh signal across the membrane. Recent structural, biochemical and cell-biological studies have converged at the surprising model that a specific pool of plasma membrane cholesterol, termed accessible cholesterol, functions as a second messenger that conveys the signal between PTCH1 and SMO. Beyond solving a central puzzle in Hh signaling, these studies are revealing new principles in membrane biology: how proteins respond to and remodel cholesterol accessibility in membranes and how the cholesterol composition of organelle membranes is used to regulate protein function.

Original languageEnglish (US)
Pages (from-to)1303-1313
Number of pages11
JournalNature chemical biology
Volume16
Issue number12
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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