Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion.
Hedgehog (Hh) is a secreted morphogen involved in both short- and long-range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We previously showed that the long-range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multivesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)-dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Of importance, oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT-derived exovesicles, which in turn act as a vehicle for long-range signaling.
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India.
Anup
A
Parchure
Institute for Stem Cell Biology and Regenerative Medicine, Tata Institute of Fundamental Research, Bangalore 560065, India.
Neha
N
Vyas
Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, University of Queensland, Brisbane St Lucia 4072, Australia.
Charles
C
Ferguson
Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, University of Queensland, Brisbane St Lucia 4072, Australia.
Robert G
RG
Parton
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India Institute for Stem Cell Biology and Regenerative Medicine, Tata Institute of Fundamental Research, Bangalore 560065, India mayor@ncbs.res.in.
Satyajit
S
Mayor
D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D004705:Endocytosis / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D060227:Imaginal Discs / Q000254:growth & development / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics; D057146:Multivesicular Bodies / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053823:Hedgehog Proteins; C077245:hh protein, Drosophila