Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway.
DSL ligands promote proteolysis of the Notch receptor, to release active Notch intracellular domain (N(ICD)). Conversely, the E3 ubiquitin ligase Deltex can activate ligand-independent Notch proteolysis and signaling. Here we show that Deltex effects require endocytic trafficking by HOPS and AP-3 complexes. Our data suggest that Deltex shunts Notch into an endocytic pathway with two possible endpoints. If Notch transits into the lysosome lumen, it is degraded. However, if HOPS and AP-3 deliver Notch to the limiting membrane of the lysosome, degradation of the Notch extracellular domain allows subsequent Presenilin-mediated release of N(ICD). This model accounts for positive and negative regulatory effects of Deltex in vivo. Indeed, we uncover HOPS/AP-3 contributions to Notch signaling during Drosophila midline formation and neurogenesis. We discuss ways in which these endocytic pathways may modulate ligand-dependent and -independent events, as a mechanism that can potentiate Notch signaling or dampen noise in the signaling network.
Wilkin
Marian
M
Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
Tongngok
Pajaree
P
Gensch
Nicole
N
Clemence
Sylvaine
S
Motoki
Masato
M
Yamada
Kenta
K
Hori
Kazuya
K
Taniguchi-Kanai
Maiko
M
Franklin
Emily
E
Matsuno
Kenji
K
Baron
Martin
M
D033963:Adaptor Protein Complex 3 / Q000378:metabolism*; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism
D033963:Adaptor Protein Complex 3; C086679:DX protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C497759:N protein, Drosophila; D051880:Receptors, Notch