Hibris, a Drosophila nephrin homolog, is required for presenilin-mediated Notch and APP-like cleavages.
Drosophila Hibris (Hbs), a member of the Nephrin Immunoglobulin Super Family, has been implicated in myogenesis and eye patterning. Here, we uncover a role of Hbs in Notch (N) signaling and γ-secretase processing. Loss of hbs results in classical N-signaling-associated phenotypes in Drosophila, including eye patterning, wing margin, and sensory organ specification defects. In particular, hbs mutant larvae display altered γ-secretase-dependent Notch proteolytic processing. Hbs also interacts molecularly and genetically with Presenilin (Psn) and other components of the γ-secretase complex. This Hbs function appears conserved, as mammalian Nephrin also promotes N signaling in mammalian cells. Our data suggest that Hbs is required for Psn maturation. Consistent with its role in Psn processing, Hbs genetically interacts with the Drosophila β-amyloid protein precursor-like (Appl) protein, the homolog of mammalian APP, the cleavage of which is associated with Alzheimer's disease. Thus, Hbs/Nephrin appear to share a general requirement in Psn/γ-secretase regulation and associated processes.
Department of Developmental & Regenerative Biology, Mount Sinai School of Medicine and Graduate School of Biological Sciences, One Gustave L. Levy Place, New York, NY 10029, USA.
Jaskirat
J
Singh
Marek
M
Mlodzik
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D056726:Genetic Association Studies; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005810:Multigene Family / Q000502:physiology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis / Q000502:physiology; D010375:Pedigree; D053763:Presenilins / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C497759:N protein, Drosophila; D053763:Presenilins; C106427:Psn protein, Drosophila; D051880:Receptors, Notch; C442230:hbs protein, Drosophila; C113267:nephrin