Autoimmune regulator

Last updated
AIRE
PBB Protein AIRE image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AIRE , AIRE1, APECED, APS1, APSI, PGA1, autoimmune regulator
External IDs OMIM: 607358 MGI: 1338803 HomoloGene: 327 GeneCards: AIRE
Orthologs
SpeciesHumanMouse
Entrez

326

11634

Ensembl

ENSG00000160224

ENSMUSG00000000731

UniProt

O43918

Q9Z0E3

RefSeq (mRNA)

NM_000383
NM_000658
NM_000659

RefSeq (protein)

NP_000374

Location (UCSC) Chr 21: 44.29 – 44.3 Mb Chr 10: 77.87 – 77.88 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. [5] It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. [6] 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. [7] 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. [5] [8] 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. [9]

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. [10] [11] 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. [12]

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. [10] This expression then allows maturing thymocytes to become tolerant towards peripheral organs, thereby suppressing autoimmune disease. [11]

The AIRE gene is expressed in many other tissues as well. [13] The AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells. [14]

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. [15] 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. [16] Another potential role for this domain is to anchor AIRE to heterologous proteins. [17] 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. [18] 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. [19]

AIRE protein rendition with both PHD fingers shown Aire protein (first- and second phd fingers).png
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. [20] 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. [21] 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. [21] Other AIRE partners include positive transcription elongation factor b (P-TEFb) and DNA activated protein kinase (DNA-PK). [22] [23] DNA-PK phosphorylates AIRE in vitro at Thr68 and Ser156. [23] 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. [24] 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. [25]

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. [26] 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. [27] Known mutations in AIRE include Arg139X, Arg257X, and Leu323SerfsX51. [28]

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. [29]

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. [30]

Interactions

Autoimmune regulator has been shown to interact with CREB binding protein. [21] [31]

See also

Related Research Articles

<span class="mw-page-title-main">Thymus</span> Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

<span class="mw-page-title-main">IPEX syndrome</span> Medical condition

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is a rare autoimmune disease. It is one of the autoimmune polyendocrine syndromes. Most often, IPEX presents with autoimmune enteropathy, dermatitis (eczema), and autoimmune endocrinopathy, but other presentations exist.

Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

<span class="mw-page-title-main">Microphthalmia-associated transcription factor</span> Mammalian protein found in Homo sapiens

Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the MITF gene.

Self-protein refers to all proteins endogenously produced by DNA-level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection, but may include those synthesized by commensal bacteria within the intestines. Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream, a breach in the skin, or a mucous membrane, may be designated as “non-self” and subsequently targeted and attacked by the immune system. Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”, the subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

<span class="mw-page-title-main">TP63</span> Protein-coding gene in the species Homo sapiens

Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.

<span class="mw-page-title-main">SOX2</span> Transcription factor gene of the SOX family

SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.

<i>CRX</i> (gene) Protein-coding gene in the species Homo sapiens

Cone-rod homeobox protein is a protein that in humans is encoded by the CRX gene.

<span class="mw-page-title-main">DLX3</span> Mammalian protein found in Homo sapiens

Homeobox protein DLX-3 is a protein that in humans is encoded by the DLX3 gene.

<span class="mw-page-title-main">FOXN1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein N1 is a protein that in humans is encoded by the FOXN1 gene.

<span class="mw-page-title-main">LZTR1</span> Protein-coding gene in the species Homo sapiens

Leucine-zipper-like transcriptional regulator 1 is a protein that in humans is encoded by the LZTR1 gene.

<span class="mw-page-title-main">Autoimmune polyendocrine syndrome type 1</span> Autoimmune condition causing dysfunction of endocrine glands

Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome. It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherited in autosomal recessive fashion due to a defect in the AIRE gene , which is located on chromosome 21 and normally confers immune tolerance.

<span class="mw-page-title-main">SAND DNA-binding protein domain</span>

In molecular biology, the protein domain SAND is named after a range of proteins in the protein family: Sp100, AIRE-1, NucP41/75, DEAF-1. It is localised in the cell nucleus and has an important function in chromatin-dependent transcriptional control. It is found solely in eukaryotes.

<span class="mw-page-title-main">Medullary thymic epithelial cells</span>

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000160224 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000731 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Aaltonen J, Björses P, Perheentupa J, Horelli-Kuitunen N, Palotie A, Peltonen L, et al. (Finnish-German APECED Consortium) (December 1997). "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains". Nature Genetics. 17 (4): 399–403. doi:10.1038/ng1297-399. PMID   9398840. S2CID   29785642.
  6. ↑ Blechschmidt K, Schweiger M, Wertz K, Poulson R, Christensen HM, Rosenthal A, et al. (February 1999). "The mouse Aire gene: comparative genomic sequencing, gene organization, and expression". Genome Research. Cold Spring Harbor Laboratory Press. 9 (2): 158–66. doi:10.1101/gr.9.2.158. OCLC   678392077. PMC   310712 . PMID   10022980.
  7. ↑ Anderson MS, Su MA (April 2011). "Aire and T cell development". Current Opinion in Immunology. 23 (2): 198–206. doi:10.1016/j.coi.2010.11.007. PMC   3073725 . PMID   21163636.
  8. ↑ Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. (December 1997). "Positional cloning of the APECED gene". Nature Genetics. 17 (4): 393–8. doi:10.1038/ng1297-393. PMID   9398839. S2CID   1583134.
  9. ↑ Heino M, Peterson P, Sillanpää N, Guérin S, Wu L, Anderson G, et al. (July 2000). "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. doi: 10.1002/1521-4141(200007)30:7<1884::aid-immu1884>3.0.co;2-p . PMID   10940877.
  10. 1 2 Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. (November 2002). "Projection of an immunological self shadow within the thymus by the aire protein". Science. 298 (5597): 1395–401. Bibcode:2002Sci...298.1395A. doi:10.1126/science.1075958. PMID   12376594. S2CID   13989491.
  11. 1 2 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (April 2003). "Aire regulates negative selection of organ-specific T cells". Nature Immunology. 4 (4): 350–4. doi:10.1038/ni906. PMID   12612579. S2CID   4561402.
  12. ↑ Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, et al. (August 2008). "Deletional tolerance mediated by extrathymic Aire-expressing cells". Science. 321 (5890): 843–7. Bibcode:2008Sci...321..843G. doi:10.1126/science.1159407. PMC   2532844 . PMID   18687966.
  13. ↑ "AIRE Gene expression/activity chart". BioGPS - your Gene Portal System. Archived from the original on 2009-12-30. Retrieved 2009-12-19.
  14. ↑ Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, et al. (May 2013). "AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment". Journal of Autoimmunity. 42: 62–70. doi:10.1016/j.jaut.2012.11.004. hdl: 10616/41469 . PMID   23265639.
  15. ↑ Perniola R, Musco G (February 2014). "The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (2): 326–37. doi: 10.1016/j.bbadis.2013.11.020 . PMID   24275490.
  16. ↑ Gibson TJ, Ramu C, Gemünd C, Aasland R (July 1998). "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. doi:10.1016/s0968-0004(98)01231-6. PMID   9697411.
  17. ↑ Carles CC, Fletcher JC (July 2010). "Missing links between histones and RNA Pol II arising from SAND?". Epigenetics. 5 (5): 381–5. doi: 10.4161/epi.5.5.11956 . PMID   20458168. S2CID   42505863.
  18. ↑ Aasland R, Gibson TJ, Stewart AF (February 1995). "The PHD finger: implications for chromatin-mediated transcriptional regulation". Trends in Biochemical Sciences. 20 (2): 56–9. doi:10.1016/s0968-0004(00)88957-4. PMID   7701562.
  19. ↑ Org T, Chignola F, Hetényi C, Gaetani M, Rebane A, Liiv I, et al. (April 2008). "The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression". EMBO Reports. 9 (4): 370–6. doi: 10.1038/embor.2008.11 . PMC   2261226 . PMID   18292755. S2CID   84265877.
  20. ↑ Kumar PG, Laloraya M, Wang CY, Ruan QG, Davoodi-Semiromi A, Kao KJ, She JX (November 2001). "The autoimmune regulator (AIRE) is a DNA-binding protein". The Journal of Biological Chemistry. 276 (44): 41357–64. doi: 10.1074/jbc.M104898200 . PMID   11533054. S2CID   27962035.
  21. 1 2 3 Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, et al. (June 2000). "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. doi:10.1074/jbc.m908944199. PMID   10748110. S2CID   2518676.
  22. ↑ Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM (December 2007). "AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells". Molecular and Cellular Biology. 27 (24): 8815–23. doi: 10.1128/MCB.01085-07 . OCLC   456127729. PMC   2169392 . PMID   17938200.
  23. 1 2 Liiv I, Rebane A, Org T, Saare M, Maslovskaja J, Kisand K, et al. (January 2008). "DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1783 (1): 74–83. doi:10.1016/j.bbamcr.2007.09.003. PMC   2225445 . PMID   17997173.
  24. ↑ Pommier Y, Sun Y, Huang SN, Nitiss JL (November 2016). "Roles of eukaryotic topoisomerases in transcription, replication and genomic stability". Nature Reviews. Molecular Cell Biology. 17 (11): 703–721. doi:10.1038/nrm.2016.111. PMC   9248348 . PMID   27649880. S2CID   39198636.
  25. ↑ Žumer K, Low AK, Jiang H, Saksela K, Peterlin BM (April 2012). "Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes". Molecular and Cellular Biology. 32 (8): 1354–62. doi:10.1128/mcb.06359-11. PMC   3318594 . PMID   22310661.
  26. ↑ Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C, et al. (August 1998). "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins". Molecular Endocrinology. 12 (8): 1112–9. doi: 10.1210/mend.12.8.0143 . PMID   9717837.
  27. ↑ Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, et al. (February 2000). "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. doi:10.1086/302765. PMC   1288090 . PMID   10677297.
  28. ↑ Fardi Golyan F, Ghaemi N, Abbaszadegan MR, Dehghan Manshadi SH, Vakili R, Druley TE, et al. (November 2019). "Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1". Immunobiology. 224 (6): 728–733. doi:10.1016/j.imbio.2019.09.004. PMID   31526676. S2CID   202671335.
  29. ↑ "OMIM".
  30. ↑ Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, et al. (February 2002). "Aire deficient mice develop multiple features of APECED phenotype and show altered immune response". Human Molecular Genetics. 11 (4): 397–409. doi: 10.1093/hmg/11.4.397 . PMID   11854172.
  31. ↑ Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T (August 2003). "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. doi:10.1359/jbmr.2003.18.8.1419. PMID   12929931. S2CID   8125330.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.