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; OMA:AIRE - orthologs
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 13kbp gene on chromosome 21q22.3 that encodes 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

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

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

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

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

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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

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  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.

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