NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

Int J Mol Sci. 2021 May 4;22(9):4872. doi: 10.3390/ijms22094872.

Abstract

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research.

Keywords: NFAT5; TonEBP; cardiovascular disease; epigenetic modification; long non-coding RNA; microRNA; signalling pathway; viral infection.

Publication types

  • Review

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology
  • DNA Methylation
  • Epigenesis, Genetic*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Response / genetics
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Kidney Medulla / metabolism
  • Kidney Medulla / pathology
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Osmolar Concentration
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Virus Diseases / genetics*
  • Virus Diseases / metabolism
  • Virus Diseases / pathology
  • Virus Diseases / virology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • A Kinase Anchor Proteins
  • AKAP13 protein, human
  • HSP70 Heat-Shock Proteins
  • Histones
  • MicroRNAs
  • Minor Histocompatibility Antigens
  • NFAT5 protein, human
  • Proto-Oncogene Proteins
  • RNA, Long Noncoding
  • Transcription Factors
  • p38 Mitogen-Activated Protein Kinases