RRC ID 70791
Author Yang S, Zhang Y, Yang C, Wu X, El Oud SM, Chen R, Cai X, Wu XS, Lan G, Zheng X.
Title Competitive coordination of the dual roles of the Hedgehog co-receptor in homophilic adhesion and signal reception.
Journal Elife
Abstract Hedgehog (Hh) signaling patterns embryonic tissues and contributes to homeostasis in adults. In Drosophila, Hh transport and signaling are thought to occur along a specialized class of actin-rich filopodia, termed cytonemes. Here, we report that Interference hedgehog (Ihog) not only forms a Hh receptor complex with Patched to mediate intracellular signaling, but Ihog also engages in trans-homophilic binding leading to cytoneme stabilization in a manner independent of its role as the Hh receptor. Both functions of Ihog (trans-homophilic binding for cytoneme stabilization and Hh binding for ligand sensing) involve a heparin-binding site on the first fibronectin repeat of the extracellular domain. Thus, the Ihog-Ihog interaction and the Hh-Ihog interaction cannot occur simultaneously for a single Ihog molecule. By combining experimental data and mathematical modeling, we determined that Hh-Ihog heterophilic interaction dominates and Hh can disrupt and displace Ihog molecules involved in trans-homophilic binding. Consequently, we proposed that the weaker Ihog-Ihog trans interaction promotes and stabilizes direct membrane contacts along cytonemes and that, as the cytoneme encounters secreted Hh ligands, the ligands trigger release of Ihog from trans Ihog-Ihog complex enabling transport or internalization of the Hh ligand-Ihog-Patched -receptor complex. Thus, the seemingly incompatible functions of Ihog in homophilic adhesion and ligand binding cooperate to assist Hh transport and reception along the cytonemes.
Volume 10
Published 2021-5-18
DOI 10.7554/eLife.65770
PII 65770
PMID 34003115
PMC PMC8131103
MeSH Animals Cell Line Drosophila Proteins / genetics* Drosophila Proteins / metabolism* Drosophila melanogaster / metabolism* Hedgehog Proteins / genetics Hedgehog Proteins / metabolism* Membrane Glycoproteins / genetics Membrane Glycoproteins / metabolism* Models, Theoretical Protein Domains Receptors, Cell Surface / genetics Receptors, Cell Surface / metabolism* Signal Transduction / physiology*
IF 7.08
Drosophila DGRC#115064