Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network.
Beta-amyloid peptides (Abeta) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the beta-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic beta-amyloid peptide, Abeta(1-40). Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic.
Shrivastava-Ranjan
Punya
P
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322-3050, USA.
Faundez
Victor
V
Fang
Guofu
G
Rees
Howard
H
Lah
James J
JJ
Levey
Allan I
AI
Kahn
Richard A
RA
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000302:isolation & purification / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000302:isolation & purification; D002352:Carrier Proteins / Q000302:isolation & purification / Q000378:metabolism*; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000302:isolation & purification; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure; D021601:trans-Golgi Network / Q000378:metabolism*
C491636:APBA2 protein, human; C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D020727:ADP-Ribosylation Factors