title: Cooperative activation of transcription by autoimmune regulator AIRE and CBP.
abstract: Autoimmune regulator (AIRE) is a transcriptional regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNbeta mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs.
authors.affiliation: Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Pitkänen
authors.forename: A
authors.initials: A
authors.lastname: Rebane
authors.forename: J
authors.initials: J
authors.lastname: Rowell
authors.forename: A
authors.initials: A
authors.lastname: Murumägi
authors.forename: P
authors.initials: P
authors.lastname: Ströbel
authors.forename: K
authors.initials: K
authors.lastname: Möll
authors.forename: M
authors.initials: M
authors.lastname: Saare
authors.forename: J
authors.initials: J
authors.lastname: Heikkilä
authors.forename: V
authors.initials: V
authors.lastname: Doucas
authors.forename: A
authors.initials: A
authors.lastname: Marx
authors.forename: P
authors.initials: P
authors.lastname: Peterson
mesh_terms: D000818:Animals; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D013950:Thymus Gland / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D000096927:AIRE Protein
chemical_list: D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000096927:AIRE Protein