Conserved cholesterol-related activities of Dispatched 1 drive Sonic hedgehog shedding from the cell membrane
| Autor: | Petra Jakobs, Uwe Kirchhefer, Dominique Manikowski, Kay Grobe, Jurij Froese, Kristina Ehring, Jonas Goretzko, Fabian Gude, Ursula Rescher |
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| Rok vydání: | 2021 |
| Předmět: |
Patched
Dispatched Cell Ligands Cell membrane Resistance–nodulation–division medicine Humans Hedgehog Proteins Sonic hedgehog Hedgehog Cells Cultured Tissue homeostasis Shedding biology Cell Membrane Membrane Transport Proteins Cell Biology Sheddase Cell biology Cholesterol medicine.anatomical_structure Ectodomain Sterol-sensing domain biology.protein Research Article Signal Transduction |
| Zdroj: | Journal of Cell Science article-version (VoR) Version of Record |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.258672 |
| Popis: | 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. Summary: The resistance–nodulation–division protein Dispatched 1 expels plasma membrane cholesterol to indirectly increase Sonic hedgehog morphogen release from the cell surface. |
| Databáze: | OpenAIRE |
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