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

被引:85
作者
Halonen, M
Kangas, H
Rüppell, T
Ilmarinen, T
Ollila, J
Kolmer, M
Vihinen, M
Palvimo, J
Saarela, J
Ulmanen, I
Eskelin, P
机构
[1] Biomedicum Helsinki, Dept Mol Med, Natl Publ Hlth Inst, Helsinki 00290, Finland
[2] Univ Helsinki Hosp, Hosp Childrens & Adolescents, Helsinki, Finland
[3] Tampere Univ, Inst Med Technol, FIN-33101 Tampere, Finland
[4] Univ Helsinki, Dept Biosci, Div Biochem, Helsinki, Finland
[5] Tampere Univ Hosp, Res Unit, Tampere, Finland
[6] Univ Helsinki, Inst Biomed, Biomed Helsinki, Helsinki, Finland
关键词
autoimmunity; mutational analysis; functional domains; protein complexes; APFCED; AIRE; APSI;
D O I
10.1002/humu.20003
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:245 / 257
页数:13
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