title: AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH.
abstract: AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well as doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells.
authors.affiliation: Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia. ingrid.liiv@ut.ee
authors.forename: Ingrid
authors.initials: I
authors.lastname: Liiv
authors.forename: Uku
authors.initials: U
authors.lastname: Haljasorg
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.forename: Julia
authors.initials: J
authors.lastname: Maslovskaja
authors.forename: Martti
authors.initials: M
authors.lastname: Laan
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000201:enzymology*; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D012642:Selegiline / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D004317:Doxorubicin; D005047:Etoposide; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D009569:Nitric Oxide; D012642:Selegiline; D014157:Transcription Factors; D000096927:AIRE Protein