Biology:Autoimmune regulator

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Short description: Immune system protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene.[1] It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids.[2] AIRE is a transcription factor expressed in the medulla (inner part) of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

Each T cell recognizes a specific antigen when it is presented in complex with a major histocompatibility complex (MHC) molecule by an antigen presenting cell. This recognition is accomplished by the T cell receptors expressed on the cell surface. T cells receptors are generated by randomly shuffled gene segments which results in a highly diverse population of T cells—each with a unique antigen specificity. Subsequently, T cells with receptors that recognize the body's own proteins need to be eliminated while still in the thymus. Through the action of AIRE, medullary thymic epithelial cells (mTEC) express major proteins from elsewhere in the body (so called "tissue-restricted antigens" - TRA) and T cells that respond to those proteins are eliminated through cell death (apoptosis). Thus AIRE drives negative selection of self-recognizing T cells.[3] When AIRE is defective, T cells that recognize antigens normally produced by the body can exit the thymus and enter circulation. This can result in a variety of autoimmune diseases.

The gene was first reported by two independent research groups Aaltonen et al. and Nagamine et al. in 1997 who were able to isolate and clone the gene from human chromosome 21q22.3. Their work was able to show that mutations in the AIRE gene are responsible for the pathogenesis of Autoimmune polyglandular syndrome type I.[1][4] More insight into the AIRE protein was later provided by Heino et al. in 2000. They showed that AIRE protein is mainly expressed in the thymic medullary epithelial cells using immunohistochemistry.[5]

Function

In the thymus, the AIRE causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus.[6][7] It is important that self-reactive T cells that bind strongly to self-antigen are eliminated in the thymus (via the process of negative selection), otherwise they may later encounter and bind to their corresponding self-antigens and initiate an autoimmune reaction. So the expression of non-local proteins by AIRE in the thymus reduces the threat of autoimmunity by promoting the elimination of auto-reactive T cells that bind antigens not normally found in the thymus. Furthermore, it has been found that AIRE is expressed in a population of stromal cells located in secondary lymphoid tissues, however these cells appear to express a distinct set of TRAs compared to mTECs.[8]

Research in knockout mice has demonstrated that AIRE functions through initiating the transcription of a diverse set of self-antigens, such as insulin, in the thymus.[6] This expression then allows maturing thymocytes to become tolerant towards peripheral organs, thereby suppressing autoimmune disease.[7]

The AIRE gene is expressed in many other tissues as well.[9] The AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.[10]

Structure

AIRE is composed of a multidomain structure that is able to bind to chromatin and act as a regulator of gene transcription. The specific makeup of AIRE includes a caspase activation and recruitment domain (CARD), nuclear localization signal (NLS), SAND domain, and two plant-homeodomain (PHD) fingers.[11] The SAND domain is located in the middle of the amino-acid chain (aa 180-280) and mediates the binding of AIRE to phosphate groups of DNA.[12] Another potential role for this domain is to anchor AIRE to heterologous proteins.[13] The two cysteine-rich PHD finger domains at the C-terminus of AIRE are PHD1 (aa 299-340) and PHD2 (aa 434-475) which are separated by a proline-rich region of amino acids.[14] These finger domains serve to read chromatin marks through the degree of methylation at the tail of histone H3. More specifically, PHD1 is able to recognize unmethylation at the H3 tail as an epigenetic mark.[15]

AIRE protein rendition with both PHD fingers shown

An integral characteristic of AIRE is its ability to homomerize into dimers and trimers which allows it to bind to specific oligonucleotide motifs.[16] This property comes from the homogeneously staining region (HSR) located at the N-terminus. Because of the α-helical four-helix bundle structure, HSR’s are sensitive to conformational changes of the gene.[17] Variants and deletions involving this domain cause an inability to activate gene transcription by preventing oligomer formation and can result in APS-1.

Mechanism

Instead of binding to consensus sequences of target gene promoters, like conventional transcription factors, AIRE engages in coordinated sequences that are performed by its multimolecular complexes. The first AIRE partner that was identified is the CREB-binding protein (CBP) that is localized in nuclear bodies and is a co-activator of many transcription factors.[17] Other AIRE partners include positive transcription elongation factor b (P-TEFb) and DNA activated protein kinase (DNA-PK).[18][19] DNA-PK phosphorylates AIRE in vitro at Thr68 and Ser156.[19] Another partner is DNA-topoisomerase (DNA-TOP) IIα. This isomerase enzyme works on DNA topology and removes positive and negative DNA supercoils by causing transient DNA breaks. In turn, this causes relaxation of local chromatin and helps the initiation and post-initiation events of gene transcription.[20] By performing double-stranded DNA breaks, DNA-TOPIIα recruits DNA-PK and poly-(ADP-ribose) polymerase (PARP1) which are involved in DNA break and repair through non-homologous end joining.[21]

Pathology

The AIRE gene is mutated in the rare autoimmune syndrome autoimmune polyendocrinopathy syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Different mutations are more common among certain populations in the world.[22] The most common exonic mutations of AIRE occur on exons 1, 2, 6, 8, and 10. Exons 1 and 2 encode the HSR, exon 6 encodes the SAND domain, exon 8 is in the PHD-1 domain, and exon 10 is located in the proline-rich region between the two PHD finger domains.[23] Known mutations in AIRE include Arg139X, Arg257X, and Leu323SerfsX51.[24]

Disruption of AIRE results in the development of a range of autoimmune diseases, the most common clinical conditions in the syndrome are hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis.[25]

A gene knockout of the murine homolog of Aire has created a transgenic mouse model that is used to study the mechanism of disease in human patients.[26]

Interactions

Autoimmune regulator has been shown to interact with CREB binding protein.[17][27]

See also

References

  1. ↑ 1.0 1.1 "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains". Nature Genetics 17 (4): 399–403. December 1997. doi:10.1038/ng1297-399. PMID 9398840. 
  2. ↑ "The mouse Aire gene: comparative genomic sequencing, gene organization, and expression". Genome Research (Cold Spring Harbor Laboratory Press) 9 (2): 158–66. February 1999. doi:10.1101/gr.9.2.158. OCLC 678392077. PMID 10022980. 
  3. ↑ "Aire and T cell development". Current Opinion in Immunology 23 (2): 198–206. April 2011. doi:10.1016/j.coi.2010.11.007. PMID 21163636. 
  4. ↑ "Positional cloning of the APECED gene". Nature Genetics 17 (4): 393–8. December 1997. doi:10.1038/ng1297-393. PMID 9398839. http://www.nature.com/articles/ng1297-393. 
  5. ↑ "RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse". European Journal of Immunology 30 (7): 1884–93. July 2000. doi:10.1002/1521-4141(200007)30:7<1884::aid-immu1884>3.0.co;2-p. PMID 10940877. 
  6. ↑ 6.0 6.1 "Projection of an immunological self shadow within the thymus by the aire protein". Science 298 (5597): 1395–401. November 2002. doi:10.1126/science.1075958. PMID 12376594. Bibcode: 2002Sci...298.1395A. 
  7. ↑ 7.0 7.1 "Aire regulates negative selection of organ-specific T cells". Nature Immunology 4 (4): 350–4. April 2003. doi:10.1038/ni906. PMID 12612579. 
  8. ↑ "Deletional tolerance mediated by extrathymic Aire-expressing cells". Science 321 (5890): 843–7. August 2008. doi:10.1126/science.1159407. PMID 18687966. Bibcode: 2008Sci...321..843G. 
  9. ↑ "AIRE Gene expression/activity chart". BioGPS - your Gene Portal System. http://biogps.gnf.org/#goto=genereport&id=326. 
  10. ↑ "AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment". Journal of Autoimmunity 42: 62–70. May 2013. doi:10.1016/j.jaut.2012.11.004. PMID 23265639. 
  11. ↑ "The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1842 (2): 326–37. February 2014. doi:10.1016/j.bbadis.2013.11.020. PMID 24275490. 
  12. ↑ "The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor". Trends in Biochemical Sciences 23 (7): 242–4. July 1998. doi:10.1016/s0968-0004(98)01231-6. PMID 9697411. 
  13. ↑ "Missing links between histones and RNA Pol II arising from SAND?". Epigenetics 5 (5): 381–5. July 2010. doi:10.4161/epi.5.5.11956. PMID 20458168. 
  14. ↑ "The PHD finger: implications for chromatin-mediated transcriptional regulation". Trends in Biochemical Sciences 20 (2): 56–9. February 1995. doi:10.1016/s0968-0004(00)88957-4. PMID 7701562. 
  15. ↑ "The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression". EMBO Reports 9 (4): 370–6. April 2008. doi:10.1038/embor.2008.11. PMID 18292755. 
  16. ↑ "The autoimmune regulator (AIRE) is a DNA-binding protein". The Journal of Biological Chemistry 276 (44): 41357–64. November 2001. doi:10.1074/jbc.M104898200. PMID 11533054. 
  17. ↑ 17.0 17.1 17.2 "The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein". The Journal of Biological Chemistry 275 (22): 16802–9. June 2000. doi:10.1074/jbc.m908944199. PMID 10748110. 
  18. ↑ "AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells". Molecular and Cellular Biology 27 (24): 8815–23. December 2007. doi:10.1128/MCB.01085-07. OCLC 456127729. PMID 17938200. 
  19. ↑ 19.0 19.1 "DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1783 (1): 74–83. January 2008. doi:10.1016/j.bbamcr.2007.09.003. PMID 17997173. 
  20. ↑ "Roles of eukaryotic topoisomerases in transcription, replication and genomic stability". Nature Reviews. Molecular Cell Biology 17 (11): 703–721. November 2016. doi:10.1038/nrm.2016.111. PMID 27649880. 
  21. ↑ "Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes". Molecular and Cellular Biology 32 (8): 1354–62. April 2012. doi:10.1128/mcb.06359-11. PMID 22310661. 
  22. ↑ "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins". Molecular Endocrinology 12 (8): 1112–9. August 1998. doi:10.1210/mend.12.8.0143. PMID 9717837. 
  23. ↑ "Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein". American Journal of Human Genetics 66 (2): 378–92. February 2000. doi:10.1086/302765. PMID 10677297. 
  24. ↑ "Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1". Immunobiology 224 (6): 728–733. November 2019. doi:10.1016/j.imbio.2019.09.004. PMID 31526676. 
  25. ↑ "OMIM". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=240300. 
  26. ↑ "Aire deficient mice develop multiple features of APECED phenotype and show altered immune response". Human Molecular Genetics 11 (4): 397–409. February 2002. doi:10.1093/hmg/11.4.397. PMID 11854172. 
  27. ↑ "P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain". Journal of Bone and Mineral Research 18 (8): 1419–29. August 2003. doi:10.1359/jbmr.2003.18.8.1419. PMID 12929931. 

Further reading

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