Abnormal signalling of 14-3-3 proteins in cells with accumulated xanthurenic acid.
Xanthurenic acid is an endogenous molecule leading to caspase-9 and -3 activation. Here we report that xanthurenic acid targets signalling proteins 14-3-3 into lysosomes leading to interruption protein/protein interaction. Xanthurenic acid changed the localisation of 14-3-3 in the cells. At a concentration of 10 and 20 microM the 14-3-3 was translocated into lysosomes. At these concentrations Bad and cofilin were dephosphorylated. Translocation of dephosphorylated Bad into mitochondria and cytochrome c release were observed. Cofilin dephosphorylation in the presence of xanthurenic acid was associated with lack of the apoptotic actin cytoskeleton disintegration. In conclusion xanthurenic acid accumulation in cells abolished the regulatory function of the proteins 14-3-3 in the cell physiology and caused misfolding of the proteins leading to cell pathology.
Malina
Halina Z
HZ
Xanthurenic Acid Laboratory, Department of Cardiology, University Hospital-Inselspital, CH-3010 Bern, Switzerland. halina.malina@dkf2.unibe.ch
Frueh
Beatrice E
BE
D048948:14-3-3 Proteins; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000378:metabolism*; D014977:Xanthurenates / Q000494:pharmacology*; D051025:bcl-Associated Death Protein
D048948:14-3-3 Proteins; C494819:BAD protein, human; D002352:Carrier Proteins; D014977:Xanthurenates; D051025:bcl-Associated Death Protein; C028330:xanthurenic acid; D045304:Cytochromes c; D014446:Tyrosine 3-Monooxygenase