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Multiple roles for lipids in the Hedgehog signalling pathway

Nature Reviews Molecular Cell Biology volume 9, pages 437–445 (2008)Cite this article

Key Points

  • Secretion of cholesterol-modified and palmitate-modified Hedgehog (Hh) might occur through the formation of multimers or by association with lipoproteins. Secretion is an active process that depends on the 12-transmembrane-domain protein Dispatched, a member of the resistance-nodulation division (RND) family of proton-driven transporters.

  • Hh signals by binding to Patched, another RND family member, and by preventing Patched repression of the G-protein-coupled receptor Smoothened. Smoothened activity is likely to be regulated by the binding of one or more small lipophilic molecules: candidates include vitamin D3 and several oxysterols.

  • Patched might repress Smoothened by regulating the availability or synthesis of small lipophilic Smoothened inhibitors.

  • Intracellular cholesterol transport is tightly regulated and the biosynthesis of different cholesterol derivatives occurs at specific subcellular locations. The similarity of Patched to the cholesterol-mobilizing transporter NPC1 suggests that it might be involved in intracellular trafficking of cholesterol or its derivatives.

Abstract

The identification of endogenous sterol derivatives that modulate the Hedgehog (Hh) signalling pathway has begun to suggest testable hypotheses for the cellular biological functions of Patched, and for the lipoprotein association of Hh. Progress in the field of intracellular sterol trafficking has emphasized how tightly the distribution of intracellular sterol is controlled, and suggests that the synthesis of sterol derivatives can be influenced by specific sterol-delivery pathways. The combination of this field with Hh studies will rapidly give us a more sophisticated understanding of both the Hh signal-transduction pathway and the cell biology of sterol metabolism.

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Figure 1: Proposed vehicles for Hedgehog release.
Figure 2: The structures of sterol-related molecules.
Figure 3: Intracellular transport of sterols and sterol derivatives.
Figure 4: Possible models for Patched-mediated Smoothened repression.

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Acknowledgements

I am grateful to T. Kurzchalia and the members of my laboratory for critical comments on this work.

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  1. Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden, 01307, Germany

    Suzanne Eaton

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Smith–Lemli–Opitz syndrome

FURTHER INFORMATION

Suzanne Eaton's homepage

Glossary

Inteins

(Protein introns). Enzymatically active domains that splice themselves out of the precursor protein, ligating the protein fragments (the 'exteins') on either side. Inteins can also ligate exteins in trans as well as in cis, and this has been exploited to modify proteins in vitro.

Raft-lipid microdomains

Small phase-separated regions of the cell membranes that are rich in cholesterol and sphingolipids. Their affinity for specific transmembrane and lipid-linked proteins, and their ability to cluster to form higher order structures have been proposed to be important for the regulation of signalling and membrane trafficking.

Cleft palate

A craniofacial abnormality that results from failure to fuse the left and right palatal shelves at the midline during embryogenesis. It can be caused by several environmental and genetic factors, including defects in Sonic Hh signalling.

Dauer formation

When starved of nutrients, the nematode worm C. elegans progresses to a unique larval form called a dauer. Dauers are long-lived and resistant to environmental insults but do not reproduce. When conditions are favourable, dauer larvae re-enter reproductive development.

ABC transporter

The many different proteins of the ABC transporter family use ATP to transport small molecules across the plasma membrane. ABCA1 has an important function in reverse cholesterol transport — effluxing cellular cholesterol to HDL particles. ABCG5 and G8 efflux cholesterol and plant sterols out of gut cells and into the gut lumen, regulating dietary sterol uptake.

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Eaton, S. Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol 9, 437–445 (2008). https://doi.org/10.1038/nrm2414

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