PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2.
Understanding the intracellular transport of the beta-amyloid precursor protein (APP) is a major key to elucidate the regulation of APP processing and thus beta-amyloid peptide generation in Alzheimer disease pathogenesis. APP and its two paralogues, APLP1 and APLP2 (APLPs), are processed in a very similar manner by the same protease activities. A putative candidate involved in APP transport is protein interacting with APP tail 1 (PAT1), which was reported to interact with the APP intracellular domain. We show that PAT1a, which is 99.0% identical to PAT1, binds to APP, APLP1, and APLP2 in vivo and describe their co-localization in trans-Golgi network vesicles or endosomes in primary neurons. We further demonstrate a direct interaction of PAT1a with the basolateral sorting signal of APP/APLPs. Moreover, we provide evidence for a direct role of PAT1a in APP/APLP transport as overexpression or RNA interference-mediated knockdown of PAT1a modulates APP/APLPs levels at the cell surface. Finally, we show that PAT1a promotes APP/APLPs processing, resulting in increased secretion of beta-amyloid peptide. Taken together, our data establish PAT1a as a functional link between APP/APLPs transport and their processing.
Kuan
Yung-Hui
YH
Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany.
Gruebl
Tomas
T
Soba
Peter
P
Eggert
Simone
S
Nesic
Iva
I
Back
Simone
S
Kirsch
Joachim
J
Beyreuther
Konrad
K
Kins
Stefan
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D027981:Symporters / Q000235:genetics / Q000502:physiology*; D022161:Transport Vesicles / Q000378:metabolism*
C466684:APBB2 protein, human; C489697:APLP1 protein, human; C084104:APLP2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D026905:Amino Acid Transport Systems; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; C475905:SLC36A1 protein, human; D027981:Symporters; D053829:Amyloid Precursor Protein Secretases