NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

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.

Figure 1

NFAT5-mediated signaling pathways under various cellular stress conditions. The various extracellular stress signals caused by hypertonic or non-hypertonic condition activate signal pathways largely through the Brx, which forms the complex with small G-protein, JIP4 and kinases MKK3/6. The complex then activates p38α-NFAT5 cascade via phosphorylation by MKK3/6. Other kinases can also phosphorylate and activate NFAT5. The phosphorylated NFAT5 translocates into nucleus, binds the TonE site of target gene promoter and initiates transcription of its target genes that response to their corresponding stimuli. Furthermore, GSK-3β, p38δ and CK1 inhibit NFAT5 activation and nuclear localization; however, AKT, PKA and PI3K can suppress the inhibitory effect of GSK-3β on NFAT5 activation by phosphorylation. In addition to kinases, other factors such as miRNA, lncRNA and epigenetic modification also regulate the AP-1-mediated NFAT5 expression and play a role in NFAT5 activation. Thin arrow: promotion; blue thick arrow: upregulation; T-shaped inhibitory arrow: inhibition. Brx: Brevis radix-like proteins; MAPK: mitogen-activated protein kinase; MKK3/6: mitogen-activated protein kinase kinase 3/6; JIP4: JNK-interacting protein 4; ERK/1/2: extracellular signal-regulated kinase1/2; Fyn: Proto-oncogene tyrosine-protein kinase Fyn; ATM: ATM serine/threonine kinase; c-Abl: tyrosine kinases c-Abl; mTOR: mechanistic target of rapamycin; AKT1: RAC-alpha serine/threonine-protein kinase; PKA: protein kinase A; PI3K: phosphoinositide 3-kinases; GSK-3β: glycogen synthase kinase 3β; CK1: casein kinase 1; TonE: tonicity-responsive enhancers; AP-1: activator protein-1; AR: aldose reductase; SMIT: sodium/myo-inositol transporter; TauT: taurine transporter; Hsp70: heat shock protein 70; iNos: inducible nitric oxide synthase; Ifnb: interferon β.