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

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• 作者：Federica Incani (1)
  Maria Luisa Serra (1)
  Alessandra Meloni (2)
  Carla Cossu (1)
  Luisella Saba (1)
  Tiziana Cabras (3)
  Irene Messana (3)
  Maria Cristina Rosatelli (1)
  
  1. Dipartimento di Sanit脿 Pubblica ; Medicina Clinica e Molecolare ; Unit脿 di Ricerca di Scienze Biomediche e Biotecnologie ; Universit脿 degli Studi di Cagliari ; via Jenner s/n ; Cagliari ; Italy
  2. Istituto di Ricerca Genetica e Biomedica ; Consiglio Nazionale delle Ricerche ; Cagliari ; Italy
  3. Dipartimento di Scienze della Vita e dell鈥橝mbiente ; Sezione di Biochimica ; Universit脿 degli Studi di Cagliari ; Cagliari ; Italy
  
• 关键词：Autoimmune regulator ; Acetylation ; Deacetylation ; Mass spectrometry ; HDAC1 ; HDAC2/SIN3A complex
• 刊名：Journal of Biomedical Science
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：21
• 期：1
• 全文大小：3,277 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Biomedicine
  
• 出版者：Springer Netherlands
• ISSN：1423-0127

文摘

Background 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. 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. Results In 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. Conclusions On 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.