title: Presenilin-1 exists in both pre- and post-Golgi compartments and recycles via COPI-coated membranes.
abstract: Presenilin-1 is involved in intramembrane proteolysis of various proteins, but its intracellular site of action has remained elusive. Here, we determined by quantitative immunogold-electron microscopy that presenilin-1 in Chinese hamster ovary cells is present in pre-Golgi compartments as well as at the plasma membrane and endosomes. Notably, a high percentage of presenilin-1 resides in COPI-coated membranes between the endoplasmic reticulum and the Golgi complex, indicating significant recycling to the endoplasmic reticulum. By contrast, the inactive aspartate mutant presenilin-1D257A is relatively excluded from COPI-coated membranes, concomitant with increased post-Golgi levels. These data provide critical evidence for the scenario that the complex containing presenilin-1 can serve as gamma-secretase at the plasma membrane or endosomes and suggest a role for COPI-mediated retrograde transport in regulating post-Golgi levels of presenilin-1.
authors.affiliation: Department of Cell Biology, University Medical Center and Institute for Biomembranes, Center for Biomedical Genetics, Utrecht University, 3584 CX Utrecht, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Réchards
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
authors.forename: Viola M J
authors.initials: VM
authors.lastname: Oorschot
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D022181:COP-Coated Vesicles / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000648:ultrastructure; D006224:Cricetinae; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D053764:Presenilin-1; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1