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

Halonen, Maria; Kangas, Hannele; Rüppell, Taina; Ilmarinen, Tanja; Ollila, Juha; Kolmer, Meelis; Vihinen, Mauno LU ; Palvimo, Jorma; Saarela, Jani and Ulmanen, Ismo, et al. (2004) In Human Mutation 23(3). p.245-257
Abstract
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... (More)
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. (Less)
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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
in
Human Mutation
volume
23
issue
3
pages
245 - 257
publisher
John Wiley & Sons
external identifiers
  • pmid:14974083
  • scopus:12144291655
ISSN
1059-7794
DOI
10.1002/humu.20003
language
English
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6ef881d6-c687-4b41-98f2-51647c322256 (old id 3635510)
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http://www.ncbi.nlm.nih.gov/pubmed/14974083?dopt=Abstract
date added to LUP
2013-06-12 16:08:42
date last changed
2017-10-01 04:59:38
@article{6ef881d6-c687-4b41-98f2-51647c322256,
  abstract     = {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.},
  author       = {Halonen, Maria and Kangas, Hannele and Rüppell, Taina and Ilmarinen, Tanja and Ollila, Juha and Kolmer, Meelis and Vihinen, Mauno and Palvimo, Jorma and Saarela, Jani and Ulmanen, Ismo and Eskelin, Petra},
  issn         = {1059-7794},
  keyword      = {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},
  language     = {eng},
  number       = {3},
  pages        = {245--257},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {APECED-causing mutations in AIRE reveal the functional domains of the protein.},
  url          = {http://dx.doi.org/10.1002/humu.20003},
  volume       = {23},
  year         = {2004},
}