title: Amyloid precursor protein traffics from the Golgi directly to early endosomes in an Arl5b- and AP4-dependent pathway.
abstract: The intracellular trafficking and proteolytic processing of the membrane-bound amyloid precursor protein (APP) are coordinated events leading to the generation of pathogenic amyloid-beta (Aβ) peptides. The membrane transport of newly synthesized APP from the Golgi to the endolysosomal system is not well defined, yet it is likely to be critical for regulating its processing by β-secretase (BACE1) and γ-secretase. Here, we show that the majority of newly synthesized APP is transported from the trans-Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface. We show that Arl5b, a small G protein localized to the TGN, and AP4 are essential for the post-Golgi transport of APP to early endosomes. Arl5b is physically associated with AP4 and is required for the recruitment of AP4, but not AP1, to the TGN. Depletion of either Arl5b or AP4 results in the accumulation of APP, but not BACE1, in the Golgi, and an increase in APP processing and Aβ secretion. These findings demonstrate that APP is diverted from BACE1 at the TGN for direct transport to early endosomes and that the TGN represents a site for APP processing with the subsequent secretion of Aβ.
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Wei Hong
authors.initials: WH
authors.lastname: Toh
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Jing Zhi A
authors.initials: JZ
authors.lastname: Tan
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Khalisah L
authors.initials: KL
authors.lastname: Zulkefli
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Houghton
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gleeson
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D016601:RNA-Binding Proteins; D022161:Transport Vesicles / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C404766:REPIN1 protein, human; D016601:RNA-Binding Proteins; D053829:Amyloid Precursor Protein Secretases; C477339:ARL5B protein, human; D020727:ADP-Ribosylation Factors
keywords: AP4; Arl5b; amyloid precursor protein; amyloid-β peptide; anterograde transport; early endosomes; trans-Golgi network