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APECED-causing mutations in AIRE reveal the functional domains of the protein.

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Author

  • Maria Halonen
  • Hannele Kangas
  • Taina Rüppell
  • Tanja Ilmarinen
  • Juha Ollila
  • Meelis Kolmer
  • Mauno Vihinen
  • Jorma Palvimo
  • Jani Saarela
  • Ismo Ulmanen
  • Petra Eskelin
Show all

Summary, in English

A defective form of the AIRE protein causes autoimmune destruction of target organs by disturbing the immunological tolerance of patients with a rare monogenic disease, autoimmune polyendocrinopathy (APE)-candidiasis (C)-ectodermal dystrophy (ED), APECED. Recently, experiments on knockout mice revealed that AIRE controls autoimmunity by regulating the transcription of peripheral tissue-restricted antigens in thymic medullary epithelial cells. Thus, AIRE provides a unique model for molecular studies of organ-specific autoimmunity. In order to analyze the molecular and cellular consequences of 16 disease-causing mutations in vitro, we studied the subcellular localization, transactivation capacity, homomultimerization, and complex formation of several mutant AIRE polypeptides. Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments. While the PHD zinc fingers were necessary for the transactivation capacity of AIRE, other regions of AIRE also modulated this function. Consequently, most of the mutations decreased transactivation. The HSR domain was responsible for the homomultimerization activity of AIRE; all the missense mutations of the HSR and the SAND domains decreased this activity, but those in other domains did not. The AIRE protein was present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturbed the formation of these complexes. In conclusion, we propose an in vitro model in which AIRE transactivates transcription through heteromeric molecular interactions that are regulated by homomultimerization and conditional localization of AIRE in the nucleus or in the cytoplasm.

Publishing year

2004

Language

English

Pages

245-257

Publication/Series

Human Mutation

Volume

23

Issue

3

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Medical Genetics

Keywords

  • Trans-Activators: metabolism
  • Trans-Activators: genetics
  • Tertiary: physiology
  • Tertiary: genetics
  • Quaternary: physiology
  • Quaternary: genetics
  • Protein Structure
  • Autoimmune: genetics
  • Polyendocrinopathies
  • Peptides: physiology
  • Peptides: metabolism
  • Peptides: genetics
  • Missense: genetics
  • Mutation
  • Mutation: physiology
  • Mutation: genetics
  • Leucine Zippers: physiology
  • Leucine Zippers: genetics
  • Intracellular Space: chemistry
  • COS Cells: cytology
  • Amino Acid Sequence: genetics
  • COS Cells: chemistry
  • Transcription Factors: chemistry
  • Transcription Factors: genetics
  • Transcription Factors: metabolism
  • Transcription Factors: physiology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1059-7794