NFAT5

Last updated
NFAT5
TonEBP-DNA complex 1IMH.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NFAT5 , NF-AT5, NFATL1, NFATZ, OREBP, TONEBP, nuclear factor of activated T-cells 5, tonicity-responsive, nuclear factor of activated T-cells 5, nuclear factor of activated T cells 5
External IDs OMIM: 604708; MGI: 1859333; HomoloGene: 4811; GeneCards: NFAT5; OMA:NFAT5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10725

54446

Ensembl

ENSG00000102908

ENSMUSG00000003847

UniProt

O94916

Q9WV30

RefSeq (mRNA)

NM_001286260
NM_018823
NM_133957

RefSeq (protein)

NP_001273189
NP_061293
NP_598718

Location (UCSC) Chr 16: 69.57 – 69.7 Mb Chr 8: 108.02 – 108.11 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Nuclear factor of activated T-cells 5, also known as NFAT5 and sometimes TonEBP, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress. [5]

Contents

The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene. [5]

Osmotic stress

Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is hypertonic, cells lose water and consequently, shrink. To counteract this, cells increase their sodium uptake in order to lose less water. However, an increase in intracellular ionic concentration is harmful to the cell. Cells can alternatively synthesize enzymes and transporters that increase intracellular concentration of organic osmolytes, which are less toxic than excess ions but which also aid in water retention. Under conditions of hyperosmolarity, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for aldose reductase (AR), the sodium chloride-betaine cotransporter (SLC6A12) the sodium/myo-inositol cotransporter (SLC5A3), the taurine transporter (SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes. [6] [7] Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production. [8]

It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla. [9] Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment. [10]

Structure

The NFAT family consists of five different forms: NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5 (this protein). The proteins in this family are expressed in nearly every tissue in the body and are known transcriptional regulators in cytokine and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system. [8] cDNA of NFAT5 was first isolated from a human brain cDNA library. Subsequent analysis revealed that NFAT5 is a member of the Rel family, which also consists of NF-κB and NFATc proteins. The largest Rel protein, it consists of nearly 1,500 amino acid residues. Like the other Rel proteins, NFAT5 contains the Rel homology domain, a conserved DNA-binding domain. Outside of the Rel homology domain, no similarities exist between NFAT5 and NF-κB or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import. [11] Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation. [8] [11] Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.

Pathway of NFAT5-Mediated Osmotic Response Activation. Upon an osmotic stress signal, Brx, localized at the cell membrane, is activated and recruits JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6, and activates p38 MAPK. p38 MAPK is necessary for naft5 expression. NFAT5 Osmotic Response Activation Pathway3.jpg
Pathway of NFAT5-Mediated Osmotic Response Activation. Upon an osmotic stress signal, Brx, localized at the cell membrane, is activated and recruits JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6, and activates p38 MAPK. p38 MAPK is necessary for naft5 expression.

Mechanism of Activation

Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane. [12] Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6. [13] This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression. [12]

It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals. [9] However, the downstream transcription of the NFAT5 gene by p38 MAPK is currently not yet characterized. It is hypothesized that p38 MAPK phosphorylation activates c-Fos and interferon regulatory factors (IRFs), which bind to AP-1-binding sites and ISRES (Interferon Stimulated Response Element) respectively. Binding to these sites consequently activates the transcription of target genes. [12]

Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.

Additional Roles

NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.

NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest. [8]

Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known.

Related Research Articles

In molecular biology, a CCAAT box is a distinct pattern of nucleotides with GGCCAATCT consensus sequence that occur upstream by 60–100 bases to the initial transcription site. The CAAT box signals the binding site for the RNA transcription factor, and is typically accompanied by a conserved consensus sequence. It is an invariant DNA sequence at about minus 70 base pairs from the origin of transcription in many eukaryotic promoters. Genes that have this element seem to require it for the gene to be transcribed in sufficient quantities. It is frequently absent from genes that encode proteins used in virtually all cells. This box along with the GC box is known for binding general transcription factors. Both of these consensus sequences belong to the regulatory promoter. Full gene expression occurs when transcription activator proteins bind to each module within the regulatory promoter. Protein specific binding is required for the CCAAT box activation. These proteins are known as CCAAT box binding proteins/CCAAT box binding factors.

<span class="mw-page-title-main">NF-κB</span> Family of transcription factor protein complexes

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

<span class="mw-page-title-main">CCAAT-enhancer-binding proteins</span> Protein family

CCAAT-enhancer-binding proteins is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators that in turn can open up chromatin structure or recruit basal transcription factors.

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 IL-2 in T cells but has since been found to play an important role in regulating many more body systems. 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.

p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Persistent activation of the p38 MAPK pathway in muscle satellite cells due to ageing, impairs muscle regeneration.

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

Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.

<span class="mw-page-title-main">MAPK14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

<span class="mw-page-title-main">CEBPB</span> Protein-coding gene in humans

CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.

<span class="mw-page-title-main">CREB1</span> Mammalian protein found in Homo sapiens

CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.

<span class="mw-page-title-main">NFATC2</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.

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

The proto-oncogene c-Rel is a protein that in humans is encoded by the REL gene. The c-Rel protein is a member of the NF-κB family of transcription factors and contains a Rel homology domain (RHD) at its N-terminus and two C-terminal transactivation domains. c-Rel is a myeloid checkpoint protein that can be targeted for treating cancer. c-Rel has an important role in B-cell survival and proliferation. The REL gene is amplified or mutated in several human B-cell lymphomas, including diffuse large B-cell lymphoma and Hodgkin's lymphoma.

<span class="mw-page-title-main">NFATC1</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the NFATC1 gene.

<span class="mw-page-title-main">MAP2K3</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.

<span class="mw-page-title-main">ATF6</span> Protein-coding gene in the species Homo sapiens

Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">GADD45G</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer.

<span class="mw-page-title-main">MAP3K4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.

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

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon, also known as NFKBIE, is a protein which in humans is encoded by the NFKBIE gene.

<span class="mw-page-title-main">MAPK13</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 13, also known as stress-activated protein kinase 4 (SAPK4), is an enzyme that in humans is encoded by the MAPK13 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000102908 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000003847 – 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 "Entrez Gene: NFAT5 nuclear factor of activated T-cells 5, tonicity-responsive".
  6. ↑ Lee SD, Choi SY, Lim SW, Lamitina ST, Ho SN, Go WY, Kwon HM (2011). "TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress: Organic osmolyte-dependent and -independent pathways". AJP: Renal Physiology. 300 (3): F707–F715. doi:10.1152/ajprenal.00227.2010. PMC   3064130 . PMID   21209002.
  7. ↑ Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM (1999). "Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity". Proc Natl Acad Sci USA. 96 (5): 2538–2542. Bibcode:1999PNAS...96.2538M. doi: 10.1073/pnas.96.5.2538 . PMC   26820 . PMID   10051678.
  8. 1 2 3 4 Lee JH, Kim M, Im YS, Choi W, Byeon SH, Lee HK (2008). "NFAT5 induction and its role in hyperosmolar stressed human limbal epithelial cells". Invest. Ophthalmol. Vis. Sci. 49 (5): 1827–1835. doi:10.1167/iovs.07-1142. PMID   18436816.
  9. 1 2 López-Rodríguez C, Antos CL, Shelton JM, Richardson JA, Lin F, Novobrantseva TI, Bronson RT, Igarashi P, Rao A, Olson EN (February 2004). "Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression". Proc. Natl. Acad. Sci. U.S.A. 101 (8): 2392–7. Bibcode:2004PNAS..101.2392L. doi: 10.1073/pnas.0308703100 . PMC   356961 . PMID   14983020.
  10. ↑ Wang Y, Ko BC, Yang JY, Lam TT, Jiang Z, Zhang J, Chung SK, Chung SS (May 2005). "Transgenic mice expressing dominant-negative osmotic-response element-binding protein (OREBP) in lens exhibit fiber cell elongation defect associated with increased DNA breaks". J. Biol. Chem. 280 (20): 19986–91. doi: 10.1074/jbc.M501689200 . PMID   15774462.
  11. 1 2 Lopez-Rodríguez C, Aramburu J, Rakeman AS, Rao A (June 1999). "NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7214–9. Bibcode:1999PNAS...96.7214L. doi: 10.1073/pnas.96.13.7214 . PMC   22056 . PMID   10377394.
  12. 1 2 3 Kino T, Takatori H, Manoli I, Wang Y, Tiulpakov A, Blackman MR, Su YA, Chrousos GP, DeCherney AH, Segars JH (2009). "Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5". Sci Signal. 2 (57): ra5. doi:10.1126/scisignal.2000081. PMC   2856329 . PMID   19211510.
  13. ↑ Kelkar N, Standen CL, Davis RJ (April 2005). "Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways". Mol. Cell. Biol. 25 (7): 2733–43. doi:10.1128/MCB.25.7.2733-2743.2005. PMC   1061651 . PMID   15767678.

Further reading

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