Conserved cholesterol-related activities of Dispatched 1 drive Sonic hedgehog shedding from the cell membrane.
Cholesterol
Dispatched
Hedgehog
Patched
Resistance–nodulation–division
Shedding
Sterol-sensing domain
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
19
03
2021
accepted:
08
07
2021
pubmed:
27
7
2021
medline:
3
2
2022
entrez:
26
7
2021
Statut:
ppublish
Résumé
The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-standing questions about this pathway include how the dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells and how the resistance-nodulation-division transporter Dispatched 1 (Disp, also known as Disp1) regulates this process. Here, we show that inactivation of Disp in Shh-expressing human cells impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. We also show that cholesterol export from Disp-deficient cells is reduced, that these cells contain increased cholesterol amounts in the plasma membrane, and that Shh shedding from Disp-deficient cells is restored by pharmacological membrane cholesterol extraction and by overexpression of transgenic Disp or the structurally related protein Patched 1 (Ptc, also known as Ptch1; a putative cholesterol transporter). These data suggest that Disp can regulate Shh function via controlled cell surface shedding and that membrane cholesterol-related molecular mechanisms shared by Disp and Ptc exercise such sheddase control.
Identifiants
pubmed: 34308968
pii: 271842
doi: 10.1242/jcs.258672
pmc: PMC8403983
pii:
doi:
Substances chimiques
DISP1 protein, human
0
Hedgehog Proteins
0
Ligands
0
Membrane Transport Proteins
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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