autoimmune regulator

{{redirect|AIRE|other uses|Aire (disambiguation){{!}}Aire}}

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene.{{cite journal | vauthors = Aaltonen J, Björses P, Perheentupa J, Horelli-Kuitunen N, Palotie A, Peltonen L, Lee YS, Francis F, Henning S, Thiel C, Leharach H | display-authors = 6 | collaboration = Finnish-German APECED Consortium | title = An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains | journal = Nature Genetics | volume = 17 | issue = 4 | pages = 399–403 | date = December 1997 | pmid = 9398840 | doi = 10.1038/ng1297-399 | s2cid = 29785642 }} It is a 13kbp gene on chromosome 21q22.3 that encodes 545 amino acids.{{cite journal | vauthors = Blechschmidt K, Schweiger M, Wertz K, Poulson R, Christensen HM, Rosenthal A, Lehrach H, Yaspo ML | display-authors = 6 | title = The mouse Aire gene: comparative genomic sequencing, gene organization, and expression | journal = Genome Research | volume = 9 | issue = 2 | pages = 158–66 | date = February 1999 | pmid = 10022980 | pmc = 310712 | publisher = Cold Spring Harbor Laboratory Press | doi = 10.1101/gr.9.2.158 | oclc = 678392077 }} AIRE is a transcription factor expressed in the medulla{{Broken anchor|date=2024-12-22|bot=User:Cewbot/log/20201008/configuration|target_link=Thymus#Medulla|reason= The anchor (Medulla) has been deleted.}} (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 (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.{{cite journal | vauthors = Anderson MS, Su MA | title = Aire and T cell development | journal = Current Opinion in Immunology | volume = 23 | issue = 2 | pages = 198–206 | date = April 2011 | pmid = 21163636 | pmc = 3073725 | doi = 10.1016/j.coi.2010.11.007 }} 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.{{cite journal | vauthors = Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N | display-authors = 6 | title = Positional cloning of the APECED gene | journal = Nature Genetics | volume = 17 | issue = 4 | pages = 393–8 | date = December 1997 | pmid = 9398839 | doi = 10.1038/ng1297-393 | url = http://www.nature.com/articles/ng1297-393 | s2cid = 1583134 }} 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.{{cite journal | vauthors = Heino M, Peterson P, Sillanpää N, Guérin S, Wu L, Anderson G, Scott HS, Antonarakis SE, Kudoh J, Shimizu N, Jenkinson EJ, Naquet P, Krohn KJ | display-authors = 6 | title = RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse | journal = European Journal of Immunology | volume = 30 | issue = 7 | pages = 1884–93 | date = July 2000 | pmid = 10940877 | doi = 10.1002/1521-4141(200007)30:7<1884::aid-immu1884>3.0.co;2-p | doi-access = free }}

Function

In the thymus, the autoimmune regulator (AIRE) induces the transcription of a broad array of organ-specific genes, resulting in the production of proteins that are normally restricted to peripheral tissues. This ectopic expression creates an "immunological self-shadow" that exposes developing T cells to peripheral antigens, thereby facilitating the negative selection of self-reactive T cells and promoting central tolerance. This discovery was achieved through the combined efforts of researchers in Diane Mathis' lab— including Mark Anderson (immunologist)—and those in the Christopher Goodnow lab, where Adrian Liston led this work.

Studies have shown that AIRE is also expressed in a subset of stromal cells in secondary lymphoid tissues, though these cells express a distinct set of tissue‐restricted antigens compared to medullary thymic epithelial cells.{{cite journal | vauthors = Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D | display-authors = 6 | title = Projection of an immunological self shadow within the thymus by the aire protein | journal = Science | volume = 298 | issue = 5597 | pages = 1395–401 | date = November 2002 | pmid = 12376594 | doi = 10.1126/science.1075958 | bibcode = 2002Sci...298.1395A | s2cid = 13989491 }}{{cite journal | vauthors = Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC | s2cid = 4561402 | title = Aire regulates negative selection of organ-specific T cells | journal = Nature Immunology | volume = 4 | issue = 4 | pages = 350–4 | date = April 2003 | pmid = 12612579 | doi = 10.1038/ni906 }} 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.{{cite journal | vauthors = Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS | display-authors = 6 | title = Deletional tolerance mediated by extrathymic Aire-expressing cells | journal = Science | volume = 321 | issue = 5890 | pages = 843–7 | date = August 2008 | pmid = 18687966 | pmc = 2532844 | doi = 10.1126/science.1159407 | bibcode = 2008Sci...321..843G }}

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

The AIRE gene is expressed in many other tissues as well.{{cite web | url = http://biogps.gnf.org/#goto=genereport&id=326 | title = AIRE Gene expression/activity chart | work = BioGPS - your Gene Portal System | access-date = 2009-12-19 | archive-url = https://web.archive.org/web/20091230141946/http://biogps.gnf.org/#goto=genereport&id=326 | archive-date = 2009-12-30 | url-status = dead }} The AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.{{cite journal | vauthors = Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, Loré K, Winqvist O, Chambers BJ, Karlsson MC | display-authors = 6 | title = AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment | journal = Journal of Autoimmunity | volume = 42 | pages = 62–70 | date = May 2013 | pmid = 23265639 | doi = 10.1016/j.jaut.2012.11.004 | hdl-access = free | hdl = 10616/41469 }}

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.{{cite journal | vauthors = Perniola R, Musco G | title = The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1842 | issue = 2 | pages = 326–37 | date = February 2014 | pmid = 24275490 | doi = 10.1016/j.bbadis.2013.11.020 | doi-access = free }} 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.{{cite journal | vauthors = Gibson TJ, Ramu C, Gemünd C, Aasland R | title = The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor | journal = Trends in Biochemical Sciences | volume = 23 | issue = 7 | pages = 242–4 | date = July 1998 | pmid = 9697411 | doi = 10.1016/s0968-0004(98)01231-6 }} Another potential role for this domain is to anchor AIRE to heterologous proteins.{{cite journal | vauthors = Carles CC, Fletcher JC | title = Missing links between histones and RNA Pol II arising from SAND? | journal = Epigenetics | volume = 5 | issue = 5 | pages = 381–5 | date = July 2010 | pmid = 20458168 | doi = 10.4161/epi.5.5.11956 | s2cid = 42505863 | doi-access = free }} 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.{{cite journal | vauthors = Aasland R, Gibson TJ, Stewart AF | title = The PHD finger: implications for chromatin-mediated transcriptional regulation | journal = Trends in Biochemical Sciences | volume = 20 | issue = 2 | pages = 56–9 | date = February 1995 | pmid = 7701562 | doi = 10.1016/s0968-0004(00)88957-4 }} 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.{{cite journal | vauthors = Org T, Chignola F, Hetényi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P | display-authors = 6 | title = The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression | journal = EMBO Reports | volume = 9 | issue = 4 | pages = 370–6 | date = April 2008 | pmid = 18292755 | doi = 10.1038/embor.2008.11 | pmc = 2261226 | s2cid = 84265877 | doi-access = free }}

File:Aire protein (first- and second phd fingers).png

An integral characteristic of AIRE is its ability to homomerize into dimers and trimers which allows it to bind to specific oligonucleotide motifs.{{cite journal | vauthors = Kumar PG, Laloraya M, Wang CY, Ruan QG, Davoodi-Semiromi A, Kao KJ, She JX | s2cid = 27962035 | title = The autoimmune regulator (AIRE) is a DNA-binding protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 44 | pages = 41357–64 | date = November 2001 | pmid = 11533054 | doi = 10.1074/jbc.M104898200 | doi-access = free }} 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.{{cite journal | vauthors = Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, Will H, Vähämurto P, Ollila J, Vihinen M, Scott HS, Antonarakis SE, Kudoh J, Shimizu N, Krohn K, Peterson P | s2cid = 2518676 | display-authors = 6 | title = The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein | journal = The Journal of Biological Chemistry | volume = 275 | issue = 22 | pages = 16802–9 | date = June 2000 | pmid = 10748110 | doi = 10.1074/jbc.m908944199 |doi-access=free }} 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. Other AIRE partners include positive transcription elongation factor b (P-TEFb) and DNA activated protein kinase (DNA-PK).{{cite journal | vauthors = Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM | title = AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells | journal = Molecular and Cellular Biology | volume = 27 | issue = 24 | pages = 8815–23 | date = December 2007 | pmid = 17938200 | doi = 10.1128/MCB.01085-07 | pmc = 2169392 | oclc = 456127729 | doi-access = free }}{{cite journal | vauthors = Liiv I, Rebane A, Org T, Saare M, Maslovskaja J, Kisand K, Juronen E, Valmu L, Bottomley MJ, Kalkkinen N, Peterson P | display-authors = 6 | title = DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1783 | issue = 1 | pages = 74–83 | date = January 2008 | pmid = 17997173 | doi = 10.1016/j.bbamcr.2007.09.003 | pmc = 2225445 }} DNA-PK phosphorylates AIRE in vitro at Thr68 and Ser156. 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.{{cite journal | vauthors = Pommier Y, Sun Y, Huang SN, Nitiss JL | s2cid = 39198636 | title = Roles of eukaryotic topoisomerases in transcription, replication and genomic stability | journal = Nature Reviews. Molecular Cell Biology | volume = 17 | issue = 11 | pages = 703–721 | date = November 2016 | pmid = 27649880 | doi = 10.1038/nrm.2016.111 | pmc = 9248348 }} 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.{{cite journal | vauthors = Žumer K, Low AK, Jiang H, Saksela K, Peterlin BM | title = Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes | journal = Molecular and Cellular Biology | volume = 32 | issue = 8 | pages = 1354–62 | date = April 2012 | pmid = 22310661 | doi = 10.1128/mcb.06359-11 | pmc = 3318594 }}

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.{{cite journal | vauthors = Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C, Cohen A, Seri M, Lerone M, Romeo G, Collin P, Salo M, Metcalfe R, Weetman A, Papasavvas MP, Rossier C, Nagamine K, Kudoh J, Shimizu N, Krohn KJ, Antonarakis SE | display-authors = 6 | title = Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins | journal = Molecular Endocrinology | volume = 12 | issue = 8 | pages = 1112–9 | date = August 1998 | pmid = 9717837 | doi = 10.1210/mend.12.8.0143 | doi-access = free }} 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.{{cite journal | vauthors = Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L | display-authors = 6 | title = Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein | journal = American Journal of Human Genetics | volume = 66 | issue = 2 | pages = 378–92 | date = February 2000 | pmid = 10677297 | doi = 10.1086/302765 | pmc = 1288090 }} Known mutations in AIRE include Arg139X, Arg257X, and Leu323SerfsX51.{{cite journal | vauthors = Fardi Golyan F, Ghaemi N, Abbaszadegan MR, Dehghan Manshadi SH, Vakili R, Druley TE, Rahimi HR, Ghahraman M | display-authors = 6 | title = Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1 | journal = Immunobiology | volume = 224 | issue = 6 | pages = 728–733 | date = November 2019 | pmid = 31526676 | doi = 10.1016/j.imbio.2019.09.004 | s2cid = 202671335 }}

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.{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=240300|title=OMIM}}

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.{{cite journal | vauthors = Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, Eskelin P, Pelto-Huikko M, Peltonen L | display-authors = 6 | title = Aire deficient mice develop multiple features of APECED phenotype and show altered immune response | journal = Human Molecular Genetics | volume = 11 | issue = 4 | pages = 397–409 | date = February 2002 | pmid = 11854172 | doi = 10.1093/hmg/11.4.397 | doi-access = free }}

Interactions

Autoimmune regulator has been shown to interact with CREB binding protein.{{cite journal | vauthors = Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T | title = 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 = Journal of Bone and Mineral Research | volume = 18 | issue = 8 | pages = 1419–29 | date = August 2003 | pmid = 12929931 | doi = 10.1359/jbmr.2003.18.8.1419 | s2cid = 8125330 }}