biostudies-literatureEhlers SFDFGDeutsche ForschungsgemeinschaftMedical Faculty of the University of Münster11https://www.ebi.ac.uk/biostudies/studies/S-EPMC11036296biostudies-literatureUnknown12(2)During their biosynthesis, Sonic hedgehog (Shh) morphogens are covalently modified by cholesterol at the C-terminus and palmitate at the N-terminus. Although both lipids initially anchor Shh to the plasma membrane of producing cells, it later translocates to the extracellular compartment to direct developmental fates in cells expressing the Patched (Ptch) receptor. Possible release mechanisms for dually lipidated Hh/Shh into the extracellular compartment are currently under intense debate. In this paper, we describe the serum-dependent conversion of the dually lipidated cellular precursor into a soluble cholesteroylated variant (Shh^C) during its release. Although Shh^C is formed in a Dispatched- and Scube2-dependent manner, suggesting the physiological relevance of theJournal of developmental biologyA Residual N-Terminal Peptide Enhances Signaling of Depalmitoylated Hedgehog to the Patched Receptor.PMC11036296SFB1348/A08GR1748/9-1MedK 20-0012GR1748/9-1, SFB1348/A08Steffes GEhring KGude FEhlers SFManikowski DGrobe KfalseA Residual N-Terminal Peptide Enhances Signaling of Depalmitoylated Hedgehog to the Patched Receptor.During their biosynthesis, Sonic hedgehog (Shh) morphogens are covalently modified by cholesterol at the C-terminus and palmitate at the N-terminus. Although both lipids initially anchor Shh to the plasma membrane of producing cells, it later translocates to the extracellular compartment to direct developmental fates in cells expressing the Patched (Ptch) receptor. Possible release mechanisms for dually lipidated Hh/Shh into the extracellular compartment are currently under intense debate. In this paper, we describe the serum-dependent conversion of the dually lipidated cellular precursor into a soluble cholesteroylated variant (Shh^C) during its release. Although Shh^C is formed in a Dispatched- and Scube2-dependent manner, suggesting the physiological relevance of the2024-01-01T00:00:00Z2024 Apr2026-04-22T03:27:11.317Z2026-04-22T03:13:10.086ZS-EPMC110362963865145610.3390/jdb12020011