J. Pitkanen et al., Subcellular localization of the autoimmune regulator protein - Characterization of nuclear targeting and transcriptional activation domain, J BIOL CHEM, 276(22), 2001, pp. 19597-19602
The autoimmune regulator (AIRE) gene, defective in the hereditary autoimmun
e disease APECED, encodes a transcriptional regulator protein. AIRE is expr
essed in the medullary epithelial cells and monocyte-dendritic cells of the
thymus with lower expression in the spleen, fetal liver, and lymph nodes.
At the cellular level, AIRE is located in microtubular structures of the cy
toskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. We
studied the determinants of the targeting of AIRE into these structures. We
report here that the N-terminal HSR domain confers localization to the mic
rotubular network whereas the C-terminal region contains a second nuclear l
ocalization signal. We also demonstrate that the consensus nuclear localiza
tion signal of AIRE is functional and that the HSR domain harbors a nuclear
export signal. Accordingly, the nuclear export inhibitor leptomycin B part
ially inhibits the nuclear export of AIRE, From a functional standpoint, we
show that AIRE can activate the interferon P minimal promoter in a transfe
ction assay and demonstrate that the transcriptional activating function of
AIRE is mediated by its two plant homeodomain (PHD) zinc fingers.