A ternary complex consisting of AICD, FE65, and TIP60 down-regulates Stathmin1.
The ternary complex consisting of AICD/FE65/TIP60 is thought to play a role in gene expression and was suggested to have a crucial impact in Alzheimer's disease. AICD is the intracellular subdomain of the amyloid precursor protein (APP) and able to bind the adapter protein FE65 and the histone acetyltransferase TIP60 setting up a nuclear dot-like phenotype. Within this work we readdressed the generation of the complex as a function of its compartments. Subsequently, we studied the proteome of AFT expressing cells vs. controls and identified Stathmin1 significantly down-regulated in AFT cells. Stathmin1 functions as an important regulatory protein of microtubule dynamics and was found associated with neurofibrillary tangles in brains of Alzheimer's disease patients. We validated our results using an independent label-free mass spectrometry based method using the same cell culture model. In a reversal model with diminished APP expression, caused by simultaneous knock-down of all three members of the APP family, we further confirmed our results, as Stathmin1 was regulated in an opposite fashion. We hypothesize that AICD-dependent deregulation of Stathmin1 causes microtubule disorganization, which might play an important role for the pathophysiology of Alzheimer's disease.
Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, D-44801 Bochum, Germany. thorsten.t.mueller@rub.de
Thorsten
T
Müller
Andreas
A
Schrötter
Christina
C
Loosse
Kathy
K
Pfeiffer
Carsten
C
Theiss
Marion
M
Kauth
Helmut E
HE
Meyer
Katrin
K
Marcus
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*
C091042:APBB1 protein, human; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C493995:STMN1 protein, human; D050777:Stathmin; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5