PAT1 induces cell death signal and SET mislocalization into the cytoplasm by increasing APP/APLP2 at the cell surface.
The cleavage of amyloid precursor protein (APP) by caspases unmasks a domain extending from membrane to caspase cleavage site. This domain induces apoptosis in vitro and in vivo when overexpressed in neurons through the help of an internalization vector. In this model, we previously showed that SET rapidly binds to the internalized domain and is involved in downstream deleterious effects. Under these conditions SET mislocalizes from the nucleus to the cytoplasm, as in Alzheimer's disease (AD). In this report using the same model, we show that PAT1 attaches to the internalized domain earlier than SET and that this binding causes an increase in the levels of APP and APLP2 at the cell surface. Down regulation experiments of PAT1 and of APP and APLP2 show that the increase of the levels of APP and APLP2 at the cell surface triggers the cell death signal and SET mislocalization into the cytoplasm. In the context of AD these data suggest that mislocalization of SET into the cytoplasm may occur downstream of first cell death signal events involving PAT1 protein.
Briand
Stéphanie
S
INSERM, U894, Université Paris-Descartes, Centre de Psychiatrie and Neuroscience, 2 ter rue d'Alésia, 75014 Paris, France.
Facchinetti
Patricia
P
Clamagirand
Christine
C
Madeira
Alexandra
A
Pommet
Jean-Michel
JM
Pimplikar
Sanjay W
SW
Allinquant
Bernadette
B
D026905:Amino Acid Transport Systems / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019921:Biotinylation / Q000379:methods; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004622:Embryo, Mammalian; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D027981:Symporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
C084104:APLP2 protein, human; D026905:Amino Acid Transport Systems; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D034741:RNA, Small Interfering; C513473:SET protein, human; C475905:SLC36A1 protein, human; D027981:Symporters; D014157:Transcription Factors; D020169:Caspases