NFAT5 Gene

The NFAT5 gene (NFAT5 stands for "Nuclear Factor Of Activated T Cells 5") is a member of the nuclear factor transcription factor family of activated T cells. protein coding gene that is located on chromosome 16q22.1. Several transcript variants have been found for this gene, coding for different isoforms.

Nuclear factor of activated T cells (NFAT5), also known as tonicity-dependent enhancer-binding protein, was originally identified as an important transcription factor involved in maintaining cellular homeostasis in hypertonic and hyperosmotic environments. The protein is a member of the nuclear transcription factor family of activated T cells. Proteins belonging to this family play a central role in inducible gene transcription during immune responses.

Although NFAT5 has been expressed and studied in various types of hyperosmolar tissues, NFAT5 has also been shown to play a role in the development and activation of immune cells, particularly T cells and macrophages. The immunoregulatory function of NFAT5 is achieved through the induction of various target genes and different signaling pathways in both tonus-dependent and -independent ways. Specifically, in response to hyperosmotic stress, NFAT5 induces the generation of pathogenic TH17 cells and pro-inflammatory macrophages, which contributes to autoimmune and inflammatory diseases. Meanwhile, NFAT5 can also be activated by tonicity-independent stimuli, including activation of Toll-like receptors and inflammatory cytokines, and promotes immune cell survival, proliferation, migration, and angiogenesis. Moreover, under isotonic conditions, NFAT5 has been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases, including rheumatoid arthritis (Lee N et al. 2019).

This protein regulates osmotic stress-induced gene expression in mammalian cells.

Furthermore, NFAT5 controls the activity of keratinocytes during osmotic stress (Muhammad K et al. 2021). Remarkably, cultured mouse keratinocytes secrete more than 300 proteins. Following ablation of NFAT5, secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), is markedly increased. This increase was found along with an increase in numerous members of the"epidermal differentiation complex" (EDC) ( Muhammad K et al. 2021; Aramburu J et al. 2019).

Unlike monomeric members of this protein family, the protein encoded by the NFAT5 gene exists as a homodimer and forms stable dimers with DNA elements.

Diseases associated with NFAT5 include:

• Inflammatory Bowel Disease-Recurrent Sinopulmonary Infections Syndrome. Inflammatory bowel disease-recurrent sinopulmonary infections syndrome is a very rare genetic immune disorder characterized by recurrent sinopulmonary infections and autoimmune enterocolopathy. It manifests as frequent episodes of intractable diarrhea with abdominal pain and fever accompanied by eczematous rashes due to deficits in components of innate and adaptive immunity. Immunologic abnormalities include IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, decreased cytokine production by CD8+ T lymphocytes, and decreased natural killer cell numbers.
• Furthermore, spinocerebellar ataxia 4 is associated with mutations in the NFAT5 gene.

1. Aramburu J et al (2019) Regulation of Inflammatory Functions of Macrophages and T Lymphocytes by NFAT5. Front Immunol 10:535.
2. Lee N et al (2019) Role of NFAT5 in the Immune System and Pathogenesis of Autoimmune Diseases. Front Immunol 10:270.
3. Muhammad K et al (2021) NFAT5 Controls the Integrity of Epidermis. Front Immunol 12:780727.