AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers

The gene responsible for autoimmune polyendocrinopathy candidiasis ectoderm al dystrophy (APECED) recently has been positionally cloned to 21q22.3, Thi s novel gene, AIRE, encodes for a predicted 57.7 kDa protein featuring two PHD-type zinc fingers shared by other proteins involved in chromatin-mediat ed transcriptional regulation. APECED is an autosomal recessive condition c haracterized by multiple polyendocrinopathies, and the typical triad of APE CED symptoms includes hypoparathyroidism, primary adrenocortical failure an d chronic mucocutaneous candidiasis, The aetiology of APECED is linked dire ctly to mutations within the coding region of AIRE. These mutations are pre dicted to lead to truncated forms of the protein lacking at least one of th e PHD zinc fingers. In this study, we have investigated the sub-cellular lo calization of AIRE expressed transiently in COS cells and fibroblasts. We f ound that AIRE has a dual nuclear and cytoplasmic localization. The wild-ty pe protein is directed to speckled domains in the nucleus and also shows co -localization with cytoskeletal filaments, N-terminal AIRE fragments delete d for the PHD domain show altered nuclear localization, suggesting that the APECED mutations may elicit their primary effects in the nucleus.