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.
Levitan
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Department of Biochemistry and Molecular Biophysics, and Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Greenwald
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I
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