Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans.
Presenilins have been implicated in the development of Alzheimer's disease and in facilitating LIN-12/Notch activity. Here, we use genetic methods to explore the relationship between C. elegans LIN-12 and SEL-12 presenilin. Reducing sel-12 activity can suppress the effects of elevated lin-12 activity when LIN-12 is activated by missense mutations but not when LIN-12 is activated by removal of the extracellular and transmembrane domains. These results suggest that SEL-12 does not function downstream of activated LIN-12. An active SEL-12::GFP hybrid protein accumulates in the perinuclear region of the vulval precursor cells (VPCs) of living hermaphrodites, consistent with a localization in endoplasmic reticulum/Golgi membranes; when sel-12 activity is reduced, less LIN-12 protein accumulates in the plasma membranes of the VPCs. Together with the genetic interactions between lin-12 and sel-12, these observations suggest a role for SEL-12 in LIN-12 processing or trafficking. However, SEL-12 does not appear to be a general factor that influences membrane protein activity, since reducing sel-12 activity does not suppress or enhance hypomorphic mutations in other genes encoding membrane proteins. We discuss potential parallels for the role of SEL-12/presenilin in facilitating LIN-12/Notch activity and in amyloid precursor protein (APP) processing.
Department of Biochemistry and Molecular Biophysics, and Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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D000483:Alleles; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins; D002450:Cell Communication; D004721:Endoplasmic Reticulum / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C082460:Lin-12 protein, C elegans; D008164:Luminescent Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C095907:SEL-12 protein, C elegans; D049452:Green Fluorescent Proteins