NFAT: Difference between revisions
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'''Nuclear factor of activated T-cells''' ('''NFAT''') is a family of [[transcription factor]]s shown to be important in [[immune response]]. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of interleukin-2 in T cells, as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems.<ref name=":1">{{Cite journal|last1=Pan|first1=M.-G.|last2=Xiong|first2=Y.|last3=Chen|first3=F.|date=2013-05-01|title=NFAT Gene Family in Inflammation and Cancer|journal=Current Molecular Medicine|language=en|volume=13|issue=4|pages=543–554|doi=10.2174/1566524011313040007|pmid=22950383|pmc=3694398}}</ref> NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders. |
'''Nuclear factor of activated T-cells''' ('''NFAT''') is a family of [[transcription factor]]s shown to be important in [[immune response]]. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of interleukin-2 in [[T cell|T cells]], as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems.<ref name=":1">{{Cite journal|last1=Pan|first1=M.-G.|last2=Xiong|first2=Y.|last3=Chen|first3=F.|date=2013-05-01|title=NFAT Gene Family in Inflammation and Cancer|journal=Current Molecular Medicine|language=en|volume=13|issue=4|pages=543–554|doi=10.2174/1566524011313040007|pmid=22950383|pmc=3694398}}</ref> NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders. |
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== Family members == |
== Family members == |
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The NFAT transcription factor family consists of five members [[NFATC1|NFATc1]], [[NFATC2|NFATc2]], [[NFATC3|NFATc3]], [[NFATC4|NFATc4]], and [[NFAT5]].<ref name="pmid11983154">{{cite journal | vauthors = Crabtree GR, Olson EN | title = NFAT signaling: choreographing the social lives of cells | journal = Cell | volume = 109 Suppl | issue = 2 | pages = S67-79 | date = April 2002 | pmid = 11983154 | doi = 10.1016/S0092-8674(02)00699-2 | s2cid = 6542642 }}</ref> NFATc1 through NFATc4 are regulated by calcium signalling, and are known as the classical members of the NFAT family. NFAT5 is a more recently discovered member of the NFAT family that has special characteristics that differentiate it from other NFAT members.<ref name=":2">{{Cite journal|last1=Macián|first1=Fernando|last2=López-Rodríguez|first2=Cristina|last3=Rao|first3=Anjana|date=April 2001|title=Partners in transcription: NFAT and AP-1|journal=Oncogene|language=En|volume=20|issue=19|pages=2476–2489|doi=10.1038/sj.onc.1204386|pmid=11402342|issn=1476-5594|doi-access=free}}</ref> |
The NFAT transcription factor family consists of five members [[NFATC1|NFATc1]], [[NFATC2|NFATc2]], [[NFATC3|NFATc3]], [[NFATC4|NFATc4]], and [[NFAT5]].<ref name="pmid11983154">{{cite journal | vauthors = Crabtree GR, Olson EN | title = NFAT signaling: choreographing the social lives of cells | journal = Cell | volume = 109 Suppl | issue = 2 | pages = S67-79 | date = April 2002 | pmid = 11983154 | doi = 10.1016/S0092-8674(02)00699-2 | s2cid = 6542642 }}</ref> NFATc1 through NFATc4 are regulated by calcium signalling, and are known as the classical members of the NFAT family. NFAT5 is a more recently discovered member of the NFAT family that has special characteristics that differentiate it from other NFAT members.<ref name=":2">{{Cite journal|last1=Macián|first1=Fernando|last2=López-Rodríguez|first2=Cristina|last3=Rao|first3=Anjana|date=April 2001|title=Partners in transcription: NFAT and AP-1|journal=Oncogene|language=En|volume=20|issue=19|pages=2476–2489|doi=10.1038/sj.onc.1204386|pmid=11402342|issn=1476-5594|doi-access=free}}</ref> |
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Calcium signalling is critical to activation of NFATc1-4 because [[calmodulin]] (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase [[calcineurin]] (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats and SP-repeats which are also present in the N-terminus of the NFAT proteins. This results in a conformational change that exposes a nuclear localization signal which promotes nuclear translocation.<ref name=":3">{{Cite journal|last=Park|first=Yune-Jung|last2=Yoo|first2=Seung-Ah|last3=Kim|first3=Mingyo|last4=Kim|first4=Wan-Uk|date=2020|title=The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases|url=https://www.frontiersin.org/articles/10.3389/fimmu.2020.00195/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FIMMU_XXXXXXXX_auto-dlvrit)|journal=Frontiers in Immunology|language=English|volume=11|doi=10.3389/fimmu.2020.00195|issn=1664-3224}}</ref> |
Calcium signalling is critical to activation of NFATc1-4 because [[calmodulin]] (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase [[calcineurin]] (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats and SP-repeats which are also present in the N-terminus of the NFAT proteins. This results in a conformational change that exposes a nuclear localization signal which promotes nuclear translocation.<ref name=":3">{{Cite journal|last=Park|first=Yune-Jung|last2=Yoo|first2=Seung-Ah|last3=Kim|first3=Mingyo|last4=Kim|first4=Wan-Uk|date=2020|title=The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases|url=https://www.frontiersin.org/articles/10.3389/fimmu.2020.00195/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FIMMU_XXXXXXXX_auto-dlvrit)|journal=Frontiers in Immunology|language=English|volume=11|doi=10.3389/fimmu.2020.00195|issn=1664-3224}}</ref> |
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On the other hand, NFAT5 lacks a crucial part of the N-terminal regulatory domain which in the aforementioned group harbours the essential CN binding site. This make NFAT5 activation completely independent of calcium signalling. It is, however, controlled by [[Map kinase|MAPK]] during osmotic stress. When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in kidney medulla, skin and eyes but it can be also found in thymus and activated lymphocytes.<ref>{{Cite journal|last=Lee|first=Jae-Ung|last2=Kim|first2=Li-Kyung|last3=Choi|first3=Je-Min|date=2018|title=Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases|url=https://www.frontiersin.org/articles/10.3389/fimmu.2018.02747/full|journal=Frontiers in Immunology|language=English|volume=9|doi=10.3389/fimmu.2018.02747|issn=1664-3224}}</ref> |
On the other hand, NFAT5 lacks a crucial part of the N-terminal regulatory domain which in the aforementioned group harbours the essential CN binding site. This make NFAT5 activation completely independent of calcium signalling. It is, however, controlled by [[Map kinase|MAPK]] during osmotic stress. When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in kidney medulla, skin and eyes but it can be also found in thymus and activated lymphocytes.<ref name=":5">{{Cite journal|last=Lee|first=Jae-Ung|last2=Kim|first2=Li-Kyung|last3=Choi|first3=Je-Min|date=2018|title=Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases|url=https://www.frontiersin.org/articles/10.3389/fimmu.2018.02747/full|journal=Frontiers in Immunology|language=English|volume=9|doi=10.3389/fimmu.2018.02747|issn=1664-3224}}</ref> |
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== Signalling and Binding == |
== Signalling and Binding == |
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=== Alternative signalling === |
=== Alternative signalling === |
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Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can be activated also by an alternative pathway. This pathay was until now proofed only for NFATc2. In this alternative activation SOCE is insignificant as shown by the fact that [[cyclosporine]] (CsA) which inhibits CN dephosporylation does not abrogate this pathway. This pathway takes place through activation of [[Interleukin-7 receptor|IL7R]] which leads to subsequent phosporylation of single |
Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can be activated also by an alternative pathway. This pathay was until now proofed only for NFATc2. In this alternative activation SOCE is insignificant as shown by the fact that [[cyclosporine]] (CsA) which inhibits CN dephosporylation does not abrogate this pathway. This pathway takes place through activation of [[Interleukin-7 receptor|IL7R]] which leads to subsequent phosporylation of single tyrosine in NFAT mediated by [[JNK3|Jnk3]] kinase a member of MAPK kinase subfamily.<ref name=":4" /> |
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=== DNA binding === |
=== DNA binding === |
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Nuclear import of NFAT and its subsequentexport is dependent on the calcium level. If the calcium level drops the export kinases in the nucleus such as [[protein kinase A|PKA]], [[Casein kinase 1|CK1]] or[[GSK-3β]] rephosphorylate NFAT. This causes that NFAT reverts into its inactive state and is exported back to the cytosol where maintenance kinases finish the rephosporylation in order to keep it in the inactivated state.<ref name=":3" /><ref>{{Citation|last=Baba|first=Yoshihiro|title=Role of Calcium Signaling in B Cell Activation and Biology|date=2016|url=https://doi.org/10.1007/82_2015_477|work=B Cell Receptor Signaling|pages=143–174|editor-last=Kurosaki|editor-first=Tomohiro|series=Current Topics in Microbiology and Immunology|place=Cham|publisher=Springer International Publishing|language=en|doi=10.1007/82_2015_477|isbn=978-3-319-26133-1|access-date=2021-05-21|last2=Kurosaki|first2=Tomohiro|editor2-last=Wienands|editor2-first=Jürgen}}</ref> |
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Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as [[protein kinase A|PKA]] and [[GSK-3β]], must be inactivated for NFAT nuclear retention.<ref name=":3" /> |
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NFAT proteins have weak DNA-binding capacity.<ref>{{Cite journal|date=2017-05-01|title=Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion|url=https://www.sciencedirect.com/science/article/abs/pii/S0143416016302329|journal=Cell Calcium|language=en|volume=63|pages=66–69|doi=10.1016/j.ceca.2017.01.014|issn=0143-4160}}</ref> Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.<ref name="pmid15928679">{{cite journal|vauthors=Macian F|date=June 2005|title=NFAT proteins: key regulators of T-cell development and function|journal=Nature Reviews. Immunology|volume=5|issue=6|pages=472–84|doi=10.1038/nri1632|pmid=15928679|s2cid=2460785}}</ref> This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signalling pathways such as ras-MAPK or PKC. In addition, this signalling integration is involved in tissue-specific gene expression during development. A screen of [[ncRNA]] sequences identified in [[Expressed sequence tag|EST]] sequencing projects<ref name="Okazaki_2002" /><ref name="pmid12819127">{{cite journal|vauthors=Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, Hayashizaki Y, Tomita M|date=June 2003|title=Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection|journal=Genome Research|volume=13|issue=6B|pages=1301–6|doi=10.1101/gr.1011603|pmc=403720|pmid=12819127}}</ref> discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called [[NRON]].<ref name="pmid16141075">{{cite journal|vauthors=Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG|date=September 2005|title=A strategy for probing the function of noncoding RNAs finds a repressor of NFAT|journal=Science|volume=309|issue=5740|pages=1570–3|bibcode=2005Sci...309.1570W|doi=10.1126/science.1115901|pmid=16141075|s2cid=22717118}}</ref> |
NFAT proteins have weak DNA-binding capacity.<ref>{{Cite journal|date=2017-05-01|title=Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion|url=https://www.sciencedirect.com/science/article/abs/pii/S0143416016302329|journal=Cell Calcium|language=en|volume=63|pages=66–69|doi=10.1016/j.ceca.2017.01.014|issn=0143-4160}}</ref> Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.<ref name="pmid15928679">{{cite journal|vauthors=Macian F|date=June 2005|title=NFAT proteins: key regulators of T-cell development and function|journal=Nature Reviews. Immunology|volume=5|issue=6|pages=472–84|doi=10.1038/nri1632|pmid=15928679|s2cid=2460785}}</ref> This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signalling pathways such as ras-MAPK or PKC. In addition, this signalling integration is involved in tissue-specific gene expression during development. A screen of [[ncRNA]] sequences identified in [[Expressed sequence tag|EST]] sequencing projects<ref name="Okazaki_2002" /><ref name="pmid12819127">{{cite journal|vauthors=Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, Hayashizaki Y, Tomita M|date=June 2003|title=Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection|journal=Genome Research|volume=13|issue=6B|pages=1301–6|doi=10.1101/gr.1011603|pmc=403720|pmid=12819127}}</ref> discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called [[NRON]].<ref name="pmid16141075">{{cite journal|vauthors=Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG|date=September 2005|title=A strategy for probing the function of noncoding RNAs finds a repressor of NFAT|journal=Science|volume=309|issue=5740|pages=1570–3|bibcode=2005Sci...309.1570W|doi=10.1126/science.1115901|pmid=16141075|s2cid=22717118}}</ref> |
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NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites which indicates that higher order synergistic interactions between relevant proteins in a cooperative complex is needed for effective transcription. The best known class of these complexes is composed of NFAT and AP-1 or other bZIP proteins. This NFAT:AP-1 complex binds to the conventional Rel-family proteins DNA binding sites and is involved in gene transcription in immune cells.<ref name=":0">{{Cite journal|last1=Rao|first1=A.|last2=Luo|first2=C.|last3=Hogan|first3=P. G.|date=1997|title=Transcription factors of the NFAT family: regulation and function|journal=Annual Review of Immunology|volume=15|pages=707–747|doi=10.1146/annurev.immunol.15.1.707|issn=0732-0582|pmid=9143705}}</ref><ref name=":2" /> |
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== NFAT function in different cell types == |
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NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites which indicates that higher order synergistic interactions between the relevant proteins in a cooperative complex is needed for effective transcription.<ref name=":0" /> |
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=== T cells === |
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T cells express almost all NFAT family members (except NFAT3) but every NFAT is important for different subpopulation of T cells.<ref name=":5" /> |
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==== Th1 ==== |
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After TCR stimulation and NFAT dephosporylation NFAT creates a complex with [[AP-1 transcription factor|AP-1]] and stimulates the production of Tbet, a key transcriptional factor for [[Th1 cell|Th1]] cells. Tbet later creates complex with NFAT as well and this complex stimulates production of IFN-γ, the most prominent cytokine of Th1 cells. The TCR activation also triggers, through NFAT:AP-1 complexe, production of NFAT2/αA which is a short isoform of NFATc2 which lacks C-terminal domain and is fulfilling a role of an autoregulator because it further enhances the activation of all [[Effector T Cell|effector T cel]]<nowiki/>l.<ref name=":4" /><ref name=":5" /> For Th1 response NFAT1 seems to be the most indispensable since knockout of NFAT1 leads to extremely skew [[Th2]] response.<ref name=":5" /> |
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The best known classes of binding sites for NFAT are the formation of a cooperative complex with [[AP-1 transcription factor|AP-1]] or other bZIP proteins and the binding to sites for conventional Rel-family proteins. NFAT5 cannot form complexes with AP-1 proteins, however all NFAT proteins recognize similar DNA binding sites in gene regulatory regions.<ref name=":2" /> |
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==== Th2 ==== |
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Activation of NFAT and AP-1 is known to be required for productive immune responses. Cooperation of NFAT with AP-1 is required for many different genes to be transcribed including IL-2, GM-CSF, IL-3, and IFN-γ. In the thymus, [[Fas ligand|FasL]] expression, which allows for potential cell death, also requires cooperation between NFAT and AP-1. This cooperation plays an important role in the cell survival or cell death checkpoint for developing [[T_cell|T cells]].<ref name=":2" /> |
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In the case of Th2 response TCR stimulation leads at first to creation of NFAT:AP-1 complex just like in TH1 response. However, under Th2 stimulation conditions this complex activates GATA3, a key transcriptional factor for Th2 cells. GATA3 subsequently also interacts with NFAT and triggers production of Th2 typical cytokines like [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]] and [[Interleukin 13|IL-13]]. NFAT2 seems to be the most important for Th2 mediated response since its impairment lowers the amount of the aforementioned cytokines and also decreeses the amount of [[IgG1]] and [[IgE]].<ref name=":5" /> |
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==== Th17 ==== |
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==== Tfh ==== |
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==== Treg cells ==== |
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=== B cells === |
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Although discovered in T cells it is becoming more obvious that NFAT is expressed also in different cell types. In B cells mainly NFATc1, NFATc2 and NFAT2/αA are expressed and fulfil important functions like antigen presentation, proliferation, and apoptosis. Although the impairment of NFAT pathway has serious consequences in T cells, in B cells they are rather mild. If for instance both STIM proteins are specifically knockout which abolishes SOCE and therefore NFAT signalling in B cells the resulting humoral response is very similar to B cells with no knockout.<ref name=":4" /> |
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=== T cell anergy and exhaustion === |
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== NFAT signalling in Neural Development == |
== NFAT signalling in Neural Development == |
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Revision as of 21:02, 21 May 2021
Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of interleukin-2 in T cells, as a regulator for T cell immune response, but has since been found to play an important role in regulating many other body systems.[1] NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.
Family members
The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4, and NFAT5.[2] NFATc1 through NFATc4 are regulated by calcium signalling, and are known as the classical members of the NFAT family. NFAT5 is a more recently discovered member of the NFAT family that has special characteristics that differentiate it from other NFAT members.[3]
Calcium signalling is critical to activation of NFATc1-4 because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats and SP-repeats which are also present in the N-terminus of the NFAT proteins. This results in a conformational change that exposes a nuclear localization signal which promotes nuclear translocation.[4]
On the other hand, NFAT5 lacks a crucial part of the N-terminal regulatory domain which in the aforementioned group harbours the essential CN binding site. This make NFAT5 activation completely independent of calcium signalling. It is, however, controlled by MAPK during osmotic stress. When a cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in kidney medulla, skin and eyes but it can be also found in thymus and activated lymphocytes.[5]
Signalling and Binding
Canonical signalling
Although phosphorylation and dephosphorylation is key for controlling NFAT function by masking and unmasking nuclear localization signals, as shown by the high number of phosphorylation sites in the NFAT regulatory domain, this dephosphorylation cannot occur without the influx of calcium ions.[1]
The classical signalling relies on activation of PLC through different receptors like TCR (PLCG1) or BCR (PLCG2). This activation leads to release of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The IP3 is especially important for calcium influx because it binds to IP3 receptor located in the membrane of ER. This cause a short sharp increase in calcium concentration in cytosol as the ions leave the ER through the IP3 receptor. [4][6]
This, however, is not enough to activate NFAT signalling. The release of calcium ions from ER is sensed by STIM proteins which are ER transmembrane proteins. Under normal circumstances the STIM proteins bind calcium ions but if most of them are released from ER the bound ions are released from the STIM proteins as well. This causes them to oligomerize and subsequently interact with ORAI1 which is an indispensable protein of CRAC complex. This complex serves as a channel which selectively allows the influx of calcium ions from outside of the cell. This phenomena is called store-operated calcium entry (SOCE). Only this longer inflow of calcium ions is capable of fully activating NFAT through CaM/CN mediated dephosphorylation as stated above.[4][6]
Alternative signalling
Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can be activated also by an alternative pathway. This pathay was until now proofed only for NFATc2. In this alternative activation SOCE is insignificant as shown by the fact that cyclosporine (CsA) which inhibits CN dephosporylation does not abrogate this pathway. This pathway takes place through activation of IL7R which leads to subsequent phosporylation of single tyrosine in NFAT mediated by Jnk3 kinase a member of MAPK kinase subfamily.[6]
DNA binding
Nuclear import of NFAT and its subsequentexport is dependent on the calcium level. If the calcium level drops the export kinases in the nucleus such as PKA, CK1 orGSK-3β rephosphorylate NFAT. This causes that NFAT reverts into its inactive state and is exported back to the cytosol where maintenance kinases finish the rephosporylation in order to keep it in the inactivated state.[4][7]
NFAT proteins have weak DNA-binding capacity.[8] Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.[9] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signalling pathways such as ras-MAPK or PKC. In addition, this signalling integration is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects[10][11] discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON.[12]
NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites which indicates that higher order synergistic interactions between relevant proteins in a cooperative complex is needed for effective transcription. The best known class of these complexes is composed of NFAT and AP-1 or other bZIP proteins. This NFAT:AP-1 complex binds to the conventional Rel-family proteins DNA binding sites and is involved in gene transcription in immune cells.[13][3]
NFAT function in different cell types
T cells
T cells express almost all NFAT family members (except NFAT3) but every NFAT is important for different subpopulation of T cells.[5]
Th1
After TCR stimulation and NFAT dephosporylation NFAT creates a complex with AP-1 and stimulates the production of Tbet, a key transcriptional factor for Th1 cells. Tbet later creates complex with NFAT as well and this complex stimulates production of IFN-γ, the most prominent cytokine of Th1 cells. The TCR activation also triggers, through NFAT:AP-1 complexe, production of NFAT2/αA which is a short isoform of NFATc2 which lacks C-terminal domain and is fulfilling a role of an autoregulator because it further enhances the activation of all effector T cell.[6][5] For Th1 response NFAT1 seems to be the most indispensable since knockout of NFAT1 leads to extremely skew Th2 response.[5]
Th2
In the case of Th2 response TCR stimulation leads at first to creation of NFAT:AP-1 complex just like in TH1 response. However, under Th2 stimulation conditions this complex activates GATA3, a key transcriptional factor for Th2 cells. GATA3 subsequently also interacts with NFAT and triggers production of Th2 typical cytokines like IL-4, IL-5 and IL-13. NFAT2 seems to be the most important for Th2 mediated response since its impairment lowers the amount of the aforementioned cytokines and also decreeses the amount of IgG1 and IgE.[5]
Th17
Tfh
Treg cells
B cells
Although discovered in T cells it is becoming more obvious that NFAT is expressed also in different cell types. In B cells mainly NFATc1, NFATc2 and NFAT2/αA are expressed and fulfil important functions like antigen presentation, proliferation, and apoptosis. Although the impairment of NFAT pathway has serious consequences in T cells, in B cells they are rather mild. If for instance both STIM proteins are specifically knockout which abolishes SOCE and therefore NFAT signalling in B cells the resulting humoral response is very similar to B cells with no knockout.[6]
T cell anergy and exhaustion
NFAT signalling in Neural Development
The Ca2+ dependent calcineurin/NFAT signalling pathway has been found to be important in neuronal growth and axon guidance during vertebrate development. Each different class of NFAT contributes to different steps in the neural development. NFAT works with neurotrophic signalling to regulate axon outgrowth in several neuronal populations. Additionally, NFAT transcription complexes integrate neuronal growth with guidance cues such as netrin to facilitate the formation of new synapses, helping to build neural circuits in the brain. NFAT is a known important player in both the developing and adult nervous system.[14]
Clinical Significance
Inflammation
NFAT plays a role in the regulation of inflammation of inflammatory bowel disease (IBD). In the gene that encodes LRRK2 (leucine-rich repeat kinase 2), a susceptibility locus for IBD was found.[15] The kinase LRRK2 is an inhibitor for the NFATc2 variety, so in mice lacking LRRK2, increased activation of NFATc2 was found in macrophages.[15] This led to an increase in the NFAT-dependent cytokines that spark severe colitis attacks.
NFAT also plays a role in Rheumatoid Arthritis (RA), an autoimmune disease that has a strong pro-inflammatory component. TNF-α, a pro-inflammatory cytokine, activates the calcineurin-NFAT pathway in macrophages. Additionally, inhibiting the mTOR pathway decreases joint inflammation and erosion, so the known interaction between mTOR pathway and NFAT presents a key to the inflammatory process of RA.[1]
As a drug target
Due to its essential role in the production of the T-cell proliferative cytokine interleukin-2, NFAT signalling is an important pharmacological target for the induction of immunosuppression. CN inhibitors, which prevent the activation of NFAT, including CsA and tacrolimus (FK506), are used in the treatment of rheumatoid arthritis, multiple sclerosis, Crohn's disease, and ulcerative colitis[16] and to prevent the rejection of organ transplants.[17] However, there is a toxicity associated with these drugs due to their ability to inhibit CN in non-immune cells, which limits their use in other situations that may call for immunosuppressing drug therapy, including allergy and inflammation.[13] There are other compounds that target NFAT directly, as opposed to targeting the phosphatase activity of calcineurin, that may have broad immunosuppressive effects but lack the toxicity of CsA and FK506. Because individual NFAT proteins exist in specific cell types or affect specific genes, it may be possible to inhibit individual NFAT protein functions for an even more selective immune effect.[13]
References
- ^ a b c Pan, M.-G.; Xiong, Y.; Chen, F. (2013-05-01). "NFAT Gene Family in Inflammation and Cancer". Current Molecular Medicine. 13 (4): 543–554. doi:10.2174/1566524011313040007. PMC 3694398. PMID 22950383.
- ^ Crabtree GR, Olson EN (April 2002). "NFAT signaling: choreographing the social lives of cells". Cell. 109 Suppl (2): S67-79. doi:10.1016/S0092-8674(02)00699-2. PMID 11983154. S2CID 6542642.
- ^ a b Macián, Fernando; López-Rodríguez, Cristina; Rao, Anjana (April 2001). "Partners in transcription: NFAT and AP-1". Oncogene. 20 (19): 2476–2489. doi:10.1038/sj.onc.1204386. ISSN 1476-5594. PMID 11402342.
- ^ a b c d Park, Yune-Jung; Yoo, Seung-Ah; Kim, Mingyo; Kim, Wan-Uk (2020). "The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases". Frontiers in Immunology. 11. doi:10.3389/fimmu.2020.00195. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c d e Lee, Jae-Ung; Kim, Li-Kyung; Choi, Je-Min (2018). "Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases". Frontiers in Immunology. 9. doi:10.3389/fimmu.2018.02747. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c d e Vaeth, Martin; Feske, Stefan (2018-03-02). "NFAT control of immune function: New Frontiers for an Abiding Trooper". F1000Research. 7. doi:10.12688/f1000research.13426.1. ISSN 2046-1402. PMC 5840618. PMID 29568499.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Baba, Yoshihiro; Kurosaki, Tomohiro (2016), Kurosaki, Tomohiro; Wienands, Jürgen (eds.), "Role of Calcium Signaling in B Cell Activation and Biology", B Cell Receptor Signaling, Current Topics in Microbiology and Immunology, Cham: Springer International Publishing, pp. 143–174, doi:10.1007/82_2015_477, ISBN 978-3-319-26133-1, retrieved 2021-05-21
- ^ "Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion". Cell Calcium. 63: 66–69. 2017-05-01. doi:10.1016/j.ceca.2017.01.014. ISSN 0143-4160.
- ^ Macian F (June 2005). "NFAT proteins: key regulators of T-cell development and function". Nature Reviews. Immunology. 5 (6): 472–84. doi:10.1038/nri1632. PMID 15928679. S2CID 2460785.
- ^ Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, et al. (December 2002). "Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs". Nature. 420 (6915): 563–73. Bibcode:2002Natur.420..563O. doi:10.1038/nature01266. PMID 12466851.
- ^ Numata K, Kanai A, Saito R, Kondo S, Adachi J, Wilming LG, Hume DA, Hayashizaki Y, Tomita M (June 2003). "Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection". Genome Research. 13 (6B): 1301–6. doi:10.1101/gr.1011603. PMC 403720. PMID 12819127. Cite error: The named reference "pmid12819127" was defined multiple times with different content (see the help page).
- ^ Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG (September 2005). "A strategy for probing the function of noncoding RNAs finds a repressor of NFAT". Science. 309 (5740): 1570–3. Bibcode:2005Sci...309.1570W. doi:10.1126/science.1115901. PMID 16141075. S2CID 22717118.
- ^ a b c Rao, A.; Luo, C.; Hogan, P. G. (1997). "Transcription factors of the NFAT family: regulation and function". Annual Review of Immunology. 15: 707–747. doi:10.1146/annurev.immunol.15.1.707. ISSN 0732-0582. PMID 9143705.
- ^ Nguyen, Tuan; Giovanni, Simone Di (2008). "NFAT signaling in neural development and axon growth". International Journal of Developmental Neuroscience. 26 (2): 141–145. doi:10.1016/j.ijdevneu.2007.10.004. PMC 2267928. PMID 18093786.
- ^ a b Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ (October 2011). "The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease". Nature Immunology. 12 (11): 1063–70. doi:10.1038/ni.2113. PMC 4140245. PMID 21983832.
- ^ Whalen K, Finkel R, Panavelil TA (2014). Pharmacology North American Edition. Lippincott Williams & Wilkins. p. 619. ISBN 978-1-4511-9177-6.
- ^ Nijkamp FP, Parnham MJ (2005). Principles of Immunopharmacology (2nd rev. and extended ed.). Basel: Birkhèauser Verlag. p. 441. ISBN 978-3-7643-5804-4.