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Cited by 68Cellular transport and secretionAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

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Prabhu, Yogikala, Burgos, Patricia V., Schindler, Christina, Farías, Ginny G., Magadán, Javier G., Bonifacino, Juan S.·2012·Molecular Biology of the Cell
DOI 10.1091/mbc.e11-11-0944PMC PMC3374752
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Abstract

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

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Authors
Prabhu, Y., Burgos, P. V., Schindler, C., Farías, G. G., Magadán, J. G., & Bonifacino, J. S.
Affiliations
  • National Institutes of Health (US)
  • Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Corresponding author
Bonifacino, Juan S.
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2012-06-15
Volume
23
Issue
12
Pages
2339-2351
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e11-11-0944
PMC
PMC3374752
OpenAlex
W2099634214
Cited by
68
References
1
Citations by year
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FWCI
3.53
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Americanae (AECID Library) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
BACE1, APP processing, adaptor protein 2, clathrin-mediated endocytosis, trans-Golgi network, endosomal trafficking, APP cleavage, brefeldin A, secretory pathway
MeSH terms
Amino Acid Sequence, Cell Membrane, Clathrin, Endocytosis, Endoplasmic Reticulum, Golgi Apparatus, HeLa Cells, Humans, Microscopy, Fluorescence, Mutation, Protein Binding, Protein Synthesis Inhibitors, Endosomes, Immunoblotting, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Brefeldin A, Two-Hybrid System Techniques, Amino Acid Motifs, Adaptor Protein Complex 2, RNA Interference, Cell Line, Tumor, Green Fluorescent Proteins, Amyloid Precursor Protein Secretases, Protein Multimerization, Proteolysis

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