NFAT5 Osmotic Response Activation Pathway3
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Nuclear factor of activated T-cells 5, also known as NFAT5 and sometimes TonEBP, is a human
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that encodes a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that regulates the expression of genes involved in the
osmotic stress Osmotic shock or osmotic stress is physiologic dysfunction caused by a sudden change in the solute concentration around a cell, which causes a rapid change in the movement of water across its cell membrane. Under hypertonic conditions - conditi ...
. The product of this gene is a member of the nuclear factors of activated
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s (
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 developme ...
) family of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s. Proteins belonging to this family play a central role in inducible gene transcription during the
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
. This protein regulates gene expression induced by
osmotic stress Osmotic shock or osmotic stress is physiologic dysfunction caused by a sudden change in the solute concentration around a cell, which causes a rapid change in the movement of water across its cell membrane. Under hypertonic conditions - conditi ...
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.


Osmotic stress

Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is
hypertonic In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membran ...
, 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
osmolyte Osmolytes are low-molecular-weight organic compounds that influence the properties of biological fluids. Osmolytes are a class of organic molecules that play a significant role in regulating osmotic pressure and maintaining cellular homeostasis in ...
s, which are less toxic than excess ions but which also aid in water retention. Under conditions of
hyperosmolarity Osmotic concentration, formerly known as osmolarity, is the measure of solute concentration, defined as the number of osmoles (Osm) of solute per litre (L) of solution (osmol/L or Osm/L). The osmolarity of a solution is usually expressed as Osm/L ...
, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for
aldose reductase In enzymology, aldose reductase (or aldehyde reductase) () is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monos ...
(AR), the sodium chloride-betaine
cotransporter Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They ...
( SLC6A12) the sodium/myo-inositol cotransporter (
SLC5A3 Sodium/myo-inositol cotransporter is a protein that in humans is encoded by the ''SLC5A3'' gene. Expression of the myo-inositol transport protein is regulated by osmotic stress. See also * Solute carrier family The solute carrier (SLC) group of ...
), the taurine transporter ( SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes. Additionally, NFAT5 induces heat shock proteins,
Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms and play crucial roles in the development of can ...
, and osmotic stress proteins. NFAT5 is also implicated in cytokine production. 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. Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.


Structure

The
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 developme ...
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 Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
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 The Rel homology domain (RHD) is a protein domain found in a family of eukaryotic transcription factors, including both NF-κB and NFAT, among others. Some of these transcription factors appear to form multi-protein DNA-bound complexes. Phosphory ...
, a conserved
DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
. Outside of the
Rel homology domain The Rel homology domain (RHD) is a protein domain found in a family of eukaryotic transcription factors, including both NF-κB and NFAT, among others. Some of these transcription factors appear to form multi-protein DNA-bound complexes. Phosphory ...
, no similarities exist between NFAT5 and
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import. Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation. Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.


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 Gef ( ), also referred to as the Talking Mongoose or the Dalby Spook, was an allegedly talking mongoose which inhabited a farmhouse owned by the Irving family, located at Cashen's Gap near the hamlet of Dalby on the Isle of Man. The story was ...
) 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. Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive
GDP Gross domestic product (GDP) is a monetary measure of the total market value of all the final goods and services produced and rendered in a specific time period by a country or countries. GDP is often used to measure the economic performance o ...
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 Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the ''MAP2K3'' gene. The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This k ...
and
MKK6 Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the ''MAP2K6'' gene, on chromosome 17. Function MAPKK 6 is a member of the ...
. This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by
Cdc42 Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...
and
Rac1 Ras-related C3 botulinum toxin substrate 1, is a protein that in humans is encoded by the ''RAC1'' gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions. Func ...
. Activation of p38 MAPK is a necessary step for NFAT5 expression. 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. 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 Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Ji ...
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. 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 Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
. 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.


References


Further reading

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External links

* * {{DEFAULTSORT:Nfat5 Transcription factors Human proteins