title: Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.
abstract: Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, England, UK.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gomez-Lamarca
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, England, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Snowdon
authors.affiliation: Institute of Genetics, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Ekatarina
authors.initials: E
authors.lastname: Seib
authors.affiliation: Institute of Genetics, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, England, UK sjb32@cam.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bray
mesh_terms: D000818:Animals; D019483:Disintegrins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008666:Metalloendopeptidases / Q000378:metabolism; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: D019483:Disintegrins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C497759:N protein, Drosophila; D051880:Receptors, Notch; C489292:Rme-8 protein, Drosophila; D033921:Vesicular Transport Proteins; C528433:Vps26 protein, Drosophila; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; C100953:KUZ protein, Drosophila; D008666:Metalloendopeptidases