autoimmune regulator; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein; APECED protein (AIRE, APECED)

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Function

transcriptional regulator that binds to DNA as a dimer or as a tetramer
binds to G-doublets in an A/T-rich environment
- the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box
binds to nucleosomes (putative)
binds to chromatin & interacts selectively with histone H3 that is not methylated at Lys-4, not phosphorylated at Thr-3 & not methylated at Arg-2
functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression
functions as a transcriptional activator & promotes expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance & the avoidance of autoimmune reactions
phosphorylated
- phosphorylation could trigger oligomerization
homodimer & homotetramer
interacts with CREBBP
interacts preferentially with histone H3 that is not methylated at Lys-4
- binds with lower affinity to histone H3 that is monomethylated at Lys-4
- trimethylation of histone H3 at Lys-4 or phosphorylation at Thr-3 abolish the interaction
binds with lower affinity to histone H3 that is acetylated at Lys-4, or that is acetylated at Lys-9 or trimethylated at Lys-9
binds histone H3 that is dimethylated at Arg-2 with very low affinity

the L-X-X-L-L repeats may be implicated in binding to nuclear receptors
the HSR domain is required for localization on tubular structures (N-terminal part) & for homodimerization
interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at Lys-4
disruption of the first PHD domain leads to reduced transcriptional activity & to localization mainly in the cytoplasm in small granules
the PHD Zn+2 fingers are necessary for transactivation capacity; however, other regions also modulate this function
contains 1 HSR domain
contains 2 PHD-type Zn+2 fingers
contains 1 SAND domain

nucleus, cytoplasm
associated with tubular structures & in discrete nuclear dots resembling ND10 nuclear bodies
may shuttle between nucleus & cytoplasm

expressed at higher level thymus

medullary epithelial cells
monocyte-dendritic cells
expressed at higher level in pancreas, adrenal cortex & testis
expressed at low level in spleen, fetal liver & lymph nodes
isoform 2 & isoform 3 seem to be less frequently expressed than isoform 1, if at all

mutations associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
most of the mutations alter the nucleus-cytoplasm distribution of AIRE & disturb its association with nuclear dots & cytoplasmic filaments
most of the mutations also decrease transactivation of the protein
the HSR domain is responsible for the homomultimerization activity of AIRE
- all the missense mutations of the HSR domain & the SAND domains decrease homomultimerization, but those in other domains do not
the AIRE protein is present in soluble HMW complexes
- mutations in the HSR domain & deletion of PHD Zn+2 fingers disturb the formation of these HMW complexes