Identification of novel interacting regions involving calcineurin and nuclear factor of activated T cells

Kitamura, Noriko; Shindo, Mayumi; Ohtsuka, Jun; Nakamura, Akira; Tanokura, Masaru; Hiroi, Takachika; Kaminuma, Osamu

doi:10.1096/fj.201902229

Cited by 6 publications

(5 citation statements)

References 42 publications

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“…This diversification may be caused by a duplication event 12 or by a vertebrate-specific translocation event 13 . However, these two clades were related to differences within the CRD 10 . CRD consists of three calcineurin-binding regions (CNBRs) with amino acid differences 9 .…”

Section: Resultsmentioning

confidence: 91%

“…Owing to such diverse functions, structural abnormalities of NFATs potentially cause various diseases 8 . In addition to providing novel information in the quest to understand diseases, differences among NFATs are considered as targets of treatment regimens 9 , 10 . However, studies on the variation and evolution of NFATs and the mechanisms involved in their diversity are limited.…”

Section: Introductionmentioning

confidence: 99%

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Evolutionary mechanisms underlying the diversification of nuclear factor of activated T cells across vertebrates

Gamboa

Kitamura

Miura

et al. 2023

Sci Rep

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The mechanisms of immunity linked to biological evolution are crucial for understanding animal morphogenesis, organogenesis, and biodiversity. The nuclear factor of activated T cells (NFAT) family consists of five members (NFATc1–c4, 5) with different functions in the immune system. However, the evolutionary dynamics of NFATs in vertebrates has not been explored. Herein, we investigated the origin and mechanisms underlying the diversification of NFATs by comparing the gene, transcript and protein sequences, and chromosome information. We defined an ancestral origin of NFATs during the bilaterian development, dated approximately 650 million years ago, where NFAT5 and NFATc1–c4 were derived independently. The conserved parallel evolution of NFATs in multiple species was probably attributed to their innate nature. Conversely, frequent gene duplications and chromosomal rearrangements in the recently evolved taxa have suggested their roles in the adaptive immune evolution. A significant correlation was observed between the chromosome rearrangements with gene duplications and the structural fixation changes in vertebrate NFATs, suggesting their role in NFAT diversification. Remarkably, a conserved gene structure around NFAT genes with vertebrate evolutionary-related breaking points indicated the inheritance of NFATs with their neighboring genes as a unit. The close relationship between NFAT diversification and vertebrate immune evolution was suggested.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Evolutionary mechanisms underlying the diversification of nuclear factor of activated T cells across vertebrates

Gamboa

Kitamura

Miura

et al. 2023

Sci Rep

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“…For immunoblot analysis, we used BHK-21 cells overexpressing EGFP-fused NFAT (22). BHK-21 cells were treated with pyrogallol (50-300 µM) for 10 min.…”

Section: Immunoblot Analysismentioning

confidence: 99%

Identification of pyrogallol from Awa-tea as an anti-allergic compound that suppresses nasal symptoms and IL-9 gene expression

et al. 2020

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As the expression level of allergic disease sensitive genes are correlated with the severity of allergic symptoms, suppression of these gene expressions could be promising therapeutics. We demonstrated that protein kinase Cδ / heat shock protein 90-mediated H1R gene expression signaling and nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression signaling are responsible for the pathogenesis of pollinosis. Treatment with Awa-tea combined with wild grape hot water extract suppressed these signaling and alleviated nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats. However, the underlying mechanism of its anti-allergic activity is not elucidated yet. Here, we sought to identify an anti-allergic compound from Awa-tea and pyrogallol was identified as an active compound. Pyrogallol strongly suppressed ionomycin-induced up-regulation of IL-9 gene expression in RBL-2H3 cells. Treatment with pyrogallol in combination with epinastine alleviated nasal symptoms and suppressed up-regulation of IL-9 gene expression in TDI-sensitized rats. Pyrogallol itself did not inhibit calcineurin phosphatase activity. However, pyrogallol suppressed ionomycin-induced dephosphorylation and nuclear translocation of NFAT. These data suggest pyrogallol is an anti-allergic compound in Awa-tea and it suppressed NFAT-mediated IL-9 gene expression through the inhibition of dephosphorylation of NFAT. This might be the underlying mechanism of the therapeutic effects of combined therapy of pyrogallol with antihistamine.

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“…T-cell receptors activate calcineurin by increasing intracellular calcium through calmodulin to elicit the T-cell response. The nuclear factor of activated T cells (NFAT) is then released from the cytosol by calcineurin, allowing for the entrance of NFAT into the nucleus, where it transactivates the expression of interleukin-2 and other cytokines ( Fellman et al, 2019 ; Kitamura et al, 2020 ). Importantly, by attaching to the cytosolic protein cyclophilin D, cyclosporine stops this process.…”

Section: Introductionmentioning

confidence: 99%

Involvement of oxidative species in cyclosporine-mediated cholestasis

et al. 2022

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Cyclosporine is an established medication for the prevention of transplant rejection. However, adverse consequences such as nephrotoxicity, hepatotoxicity, and cholestasis have been associated with prolonged usage. In cyclosporine-induced obstructive and chronic cholestasis, for example, the overproduction of oxidative stress is significantly increased. Additionally, cyclosporine exerts adverse effects on liver function and redox balance responses in treated rats, as evidenced by its increasing levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin while also decreasing the levels of glutathione and NADPH. Cyclosporine binds to cyclophilin to produce its therapeutic effects, and the resulting complex inhibits calcineurin, causing calcium to accumulate in the mitochondria. Accumulating calcium with concomitant mitochondrial abnormalities induces oxidative stress, perturbation in ATP balance, and failure of calcium pumps. Also, cyclosporine-induced phagocyte oxidative stress generation via the interaction of phagocytes with Toll-like receptor-4 has been studied. The adverse effect of cyclosporine may be amplified by the release of mitochondrial DNA, mediated by oxidative stress-induced mitochondrial damage. Given the uncertainty surrounding the mechanism of cyclosporine-induced oxidative stress in cholestasis, we aim to illuminate the involvement of oxidative stress in cyclosporine-mediated cholestasis and also explore possible strategic interventions that may be applied in the future.

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Identification of novel interacting regions involving calcineurin and nuclear factor of activated T cells

Cited by 6 publications

References 42 publications

Evolutionary mechanisms underlying the diversification of nuclear factor of activated T cells across vertebrates

Evolutionary mechanisms underlying the diversification of nuclear factor of activated T cells across vertebrates

Identification of pyrogallol from Awa-tea as an anti-allergic compound that suppresses nasal symptoms and IL-9 gene expression

Involvement of oxidative species in cyclosporine-mediated cholestasis

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