Abstract
BackgroundThe AIRE protein plays a remarkable role as a regulator of central tolerance by controlling the promiscuous expression of tissue-specific antigens in thymic medullary epithelial cells. Defects in AIRE gene cause the autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy, a rare disease frequent in Iranian Jews, Finns, and Sardinian population.AIRE protein is primarily known as a transcriptional regulator and is capable of interacting with numerous proteins. The first characterized partner of AIRE is the ubiquitous transcription factor CREB-binding protein (CBP), which regulates DNA transcription through the acetylation and deacetylation of histones. More recently, the role of p300 in AIRE acetylation, which could influence the selection of AIRE activated genes, has been described.ResultsIn this study, we have precisely mapped, by mass spectrometry experiments, the sites of protein acetylation and, by mutagenesis assays, we have described a set of acetylated lysines as being crucial in influencing the subcellular localization of AIRE. Furthermore, we have also determined that the de-acetyltransferase enzymes HDAC1-2 are involved in the lysine de-acetylation of AIRE.ConclusionsOn the basis of our results and those reported in literature, we propose a model in which lysines acetylation increases the stability of AIRE in the nucleus. In addition, we observed that the interaction of AIRE with deacetylases complexes inhibits its transcriptional activity and is probably responsible for the instability of AIRE, which becomes more susceptible to degradation in the proteasome.
Highlights
The autoimmune regulator (AIRE) protein plays a remarkable role as a regulator of central tolerance by controlling the promiscuous expression of tissue-specific antigens in thymic medullary epithelial cells
Acetylation of AIRE nuclear localization signal (NLS) domain is required for the correct nuclear localization It is well-established that lysine acetylation in the NLS domain regulates the distribution of several proteins
In our previous work [23], we demonstrated that AIRE interacts with endogenous histone deacetylase 1 and histone deacetylase 2 (HDAC1, HDAC2), two targets for epigenetic repression that play an important role in transcriptional regulation through the deacetylation of histonic lysines
Summary
The AIRE protein plays a remarkable role as a regulator of central tolerance by controlling the promiscuous expression of tissue-specific antigens in thymic medullary epithelial cells. The AIRE protein induces the expression of a battery of peripheral tissue self-antigens (PTAs) in thymic stromal cells, promoting the clonal deletion of differentiating T cells that recognize them [1]. For this reason, the study of the function of AIRE protein represents. AIRE is mainly localized in the nucleus, where it assembles in aggregates called nuclear bodies It is characterized by several domains involved in nuclear transport, in transcriptional activation, in DNA binding, in E3 ubiquitin ligase activity and in transcriptional repression. This finding is supported by the presence in this region of an APECED causing mutation [3]
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