NFAT

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 signaling, 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 signaling is critical to NFAT activation because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats in the amino termini of NFAT proteins, resulting in a conformational change that exposes a nuclear localization signal, resulting in NFAT nuclear import.

NFATc1 and NFAT c2 mRNAs are expressed in peripheral lymphoid tissue, while NFATc4 is highly expressed in the thymus. NFATc3 mRNA however, is expressed at low levels in lymphoid tissue.[4]

Signaling and Binding

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.[1]

Nuclear import of NFAT proteins is opposed by maintenance kinases in the cytoplasm and export kinases in the nucleus. Export kinases, such as PKA and GSK-3β, must be inactivated for NFAT nuclear retention.

NFAT proteins have weak DNA-binding capacity. Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn.[5] This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signaling pathways such as ras-MAPK or PKC. In addition, this signaling integration is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects[6][7] discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON.[8]

The best known classes of binding sites for NFAT are the formation of a cooperative complex with AP-1 or other bZIP proteins to form a composite NFAT:AP-1 site that is involved in gene transcription in immune cells and the binding to sites for conventional Rel-family proteins.[9]

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.[9]

NFAT and AP-1

The best known classes of binding sites for NFAT are the formation of a cooperative complex with 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.[3]

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, 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 cells.[3]

NFAT signaling in Neural Development

The Ca2+ dependent calcineurin/NFAT signaling 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 signaling 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.[10]

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.[11] The kinase LRRK2 is an inhibitor for the NFATc2 variety, so in mice lacking LRRK2, increased activation of NFATc2 was found in macrophages.[11] 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 signaling is an important pharmacological target for the induction of immunosuppression. CN inhibitors, which prevent the activation of NFAT, including cyclosporine (CsA) and tacrolimus (FK506), are used in the treatment of rheumatoid arthritis, multiple sclerosis, Crohn's disease, and ulcerative colitis[12] and to prevent the rejection of organ transplants.[13] 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.[9] 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.[9]

References
  1. 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.
  2. 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.
  3. 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.
  4. Rao, Anjana; Luo, Chun; Hogan, Patrick (April 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. PMID 9143705.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. Whalen K, Finkel R, Panavelil TA (2014). Pharmacology North American Edition. Lippincott Williams & Wilkins. p. 619. ISBN 978-1-4511-9177-6.
  13. Nijkamp FP, Parnham MJ (2005). Principles of Immunopharmacology (2nd rev. and extended ed.). Basel: Birkhèauser Verlag. p. 441. ISBN 978-3-7643-5804-4.
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