GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network.
Golgi-localized, gamma ear-containing, ADP ribosylation factor-binding (GGA) proteins have been shown to be implicated in the sorting of cargo proteins from the trans-Golgi network (TGN) to endosomal compartments. GGAs directly bind to DXXLL motifs in the cytoplasmic domains of cargo proteins. The Alzheimer-associated beta-secretase BACE1 also interacts with GGA proteins, but the functional relevance of this interaction was unknown. Here, we show that GGA1 regulates the retrograde transport of internalized BACE1 from endosomal compartments to the TGN by direct interaction in a phosphorylation-dependent manner. While phosphorylated BACE1 is efficiently transported from endosomes to the TGN, non-phosphorylated BACE1 enters a direct recycling route to the cell surface. Our data indicate that GGA proteins are not only involved in the sorting at the TGN but also mediate the retrograde transport of cargo proteins from endosomes to the TGN.
Wahle
Tina
T
Department of Neurology, Laboratory of Molecular Cell Biology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Prager
Kai
K
Raffler
Nikolai
N
Haass
Christian
C
Famulok
Michael
M
Walter
Jochen
J
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D010450:Endopeptidases; D011992:Endosomes / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D021601:trans-Golgi Network / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D020727:ADP-Ribosylation Factors