AATF inhibits aberrant production of amyloid beta peptide 1-42 by interacting directly with Par-4.
Aggregation of the neurotoxic amyloid beta peptide 1-42 (Abeta-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased production of Abeta-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of beta-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Abeta in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions.
Guo
Qing
Q
Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. qing-guo@ouhsc.edu
Xie
Jun
J
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016350:Leucine Zippers; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C402637:AATF protein, human; D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C101296:prostate apoptosis response-4 protein