Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila

The transmembrane glycoprotein Nicastrin was identified in a complex with the multipass membrane protein Presenilin(1). Presenilin mediates transmembrane cleavage of single-pass transmembrane proteins with short extracellular domains(2), including the ligand-activated form of the receptor Notch(3-5) and beta -amyloid precursor protein (beta -APP)(6,7). Transmembrane cleavage of Notch is essential for signal transduction(3-5), and transmembrane cleavage of beta -APP generates pathogenic amyloid peptides implicated in Alzheimer's disease(8). Here, we investigate the requirement for Nicastrin in Presenilin-mediated transmembrane cleavage. We show that, in Drosophila, loss of Nicastrin activity blocks the accumulation of Presenilin associated with the apical plasma membrane, abolishes Presenilin-dependent cleavage of the transmembrane domains of Notch and beta -APP, and abrogates Notch signal transduction.