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The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin α molecules
Author(s) -
Ilmarinen Tanja,
Melén Krister,
Kangas Hannele,
Julkunen Ilkka,
Ulmanen Ismo,
Eskelin Petra
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2005.05065.x
Subject(s) - nls , importin , nuclear localization sequence , nuclear transport , biology , nuclear protein , microbiology and biotechnology , regulator , nuclear pore , autoimmune regulator , cell nucleus , genetics , gene , cytoplasm , transcription factor
Autoimmune regulator (AIRE) is a transcriptional regulator involved in establishing immunological self‐tolerance. Mutations in the AIRE gene lead to the development of the autosomal, recessively inherited, organ‐specific autoimmune disease, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). The AIRE protein is mainly localized in the cell nucleus where it is associated with nuclear bodies. The N‐terminal part of AIRE has been previously shown to mediate nuclear localization of the protein. However, the functional nuclear localization signal (NLS) and nuclear import mechanisms of AIRE have not been identified. We show that, although the amino‐acid sequence of AIRE contains a potential bipartite NLS consisting of amino acids 110–114 and 131–133, only the latter part constitutes a functional NLS. Furthermore, we show by in vitro binding assays that AIRE interacts with multiple members of the nuclear transport receptor importin α family, mainly α1, α3, and α5, and that these interactions depend on the intactness of the Arg‐Lys‐rich NLS of AIRE. In addition, we found that AIRE binds to the ‘minor’ NLS‐binding site of importin α3 and α5 proteins consisting of the C‐terminal armadillo repeats 7–9. Our findings strongly suggest that the nuclear import of AIRE is mediated by the classical importin α/β pathway through binding to several importin α family members.