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- Title
CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids.
- Authors
Lo, Megan; Sharir, Amnon; Paul, Michael D.; Torosyan, Hayarpi; Agnew, Christopher; Li, Amy; Neben, Cynthia; Marangoni, Pauline; Xu, Libin; Raleigh, David R.; Jura, Natalia; Klein, Ophir D.
- Abstract
The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can lead to congenital malformations and diseases including cancer. Although cholesterol and several oxysterol lipids have been shown to play crucial roles in HH activation, the molecular mechanisms governing their regulation remain unresolved. Here, we identify Canopy4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that modulates levels of membrane sterol lipids. Cnpy4–/– embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway in vitro and elevates membrane levels of accessible sterol lipids, such as cholesterol, an endogenous ligand involved in HH activation. Our data demonstrate that CNPY4 is a negative regulator that fine-tunes HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition. Although lipids are known to affect Hedgehog (Hh) signalling, the underlying mechanisms remain unclear. Here, the authors show that Canopy4 regulates membrane sterol lipid levels, with knockout mouse embryos exhibiting digit number changes and other Hh signalling-related developmental defects.
- Subjects
MEMBRANE lipids; HEDGEHOG signaling proteins; HYDROXYCHOLESTEROLS; CELLULAR signal transduction; ADULT development; HUMAN abnormalities
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30186-x