PT  - JOURNAL ARTICLE
AU  - K. Ehring
AU  - D. Manikowski
AU  - J. Froese
AU  - J. Goretzko
AU  - P. Jakobs
AU  - F. Gude
AU  - U. Rescher
AU  - K. Grobe
TI  - Conserved cholesterol-related activities of Dispatched drive Sonic hedgehog shedding from the cell membrane
AID  - 10.1101/2020.10.19.346395
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.19.346395
4099  - http://biorxiv.org/content/early/2020/10/20/2020.10.19.346395.short
4100  - http://biorxiv.org/content/early/2020/10/20/2020.10.19.346395.full
AB  - The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how 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 (Disp) regulates this process. Here we show that Disp inactivation in Shh expressing cells specifically impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. Shh shedding from Disp-deficient cells was restored by pharmacological membrane cholesterol extraction and by overexpressed transgenic Disp or structurally related Patched (Ptc, a putative cholesterol transporter). These data suggest that Disp regulates physiological Shh function via controlled cell surface shedding and that molecular mechanisms shared by Disp and Ptc exercise such sheddase control.