AIRE acetylation and deacetylation: effect on protein stability and transactivation activity

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.

Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

“…We identified five interaction partners, two of which, PIAS1 and Ubc9, had been previously reported to interact with Aire (33,34). We provide evidence that HIPK2, a known regulator of cell fate and transcription, is a novel Aire binding protein, adding to the growing list of Aire binding partners and Aire "allies" (7-9, 12, 16, 17).…”

“…HIPK2 interacts with CBP and stimulates the acetyltransferase activity of CBP/p300 (36,45). Remarkably, acetylation has been shown to affect different aspects of the function of Aire, that is, the selection of target genes (46), protein stability, and nuclear localization (34). The tripartite interaction between Aire, HIPK2, and CBP may thus stimulate Aire acetylation and phosphorylation, with the latter leading to suppression of coactivator activity in vitro.…”

AIRE expands: new roles in immune tolerance and beyond

“…More recent reports have suggested additional partners and/or functions as well as provided confirmation of earlier findings (Figure 3A). For instance, interacting proteins have been described that help Aire to recognize and target TSA genes 25–30 , release stalled RNA polymerase to allow RNA elongation 24, 31–33 , and regulate Aire itself 34–38 . Additionally, inroads have been made into mapping the regions of Aire that bind to interacting partners 25, 38, 39 (Figure 3B).…”

“…Interestingly, Aire interacts with a number of proteins that exert control over Aire’s function through post-translational modifications 34–38 . First, Aire associates with deacetylase and acetyltransferase proteins that act directly upon Aire 34–36 .…”

“…First, Aire associates with deacetylase and acetyltransferase proteins that act directly upon Aire 34–36 . For instance, Aire physically binds to Sirtuin 1 (Sirt1), a protein deacetylase that is highly expressed within mTECs (Figure 3A) 36 .…”