Can 14-3-3 proteins serve as therapeutic targets for the treatment of metabolic diseases?

Diallo, Kadidia; Oppong, Abel; Lim, Gareth E.

doi:10.1016/j.phrs.2018.11.021

Cited by 32 publications

(25 citation statements)

References 137 publications

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“…, lower) , a member of the 14‐3‐3 family. The seven isoforms (β, γ, ε, η, σ, τ/θ, and ζ ) of these highly conserved soluble acidic proteins have been assigned multiple roles as adapter proteins, localization anchors, or regulators of enzymatic activity , besides regulating intracellular signaling pathways, such as signal transduction, protein trafficking, cell cycle, apoptosis, and stress responses . Only the ε and ζ isoforms are able to interact with Apaf‐1, with the interaction with 14‐3‐3ε being much stronger .…”

Section: Cytochrome C In the Cytoplasm: Established And New Targetsmentioning

confidence: 99%

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

et al. 2019

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Cytochrome c (Cc) is a protein that functions as an electron carrier in the mitochondrial respiratory chain. However, Cc has moonlighting roles outside mitochondria driving the transition of apoptotic cells from life to death. When living cells are damaged, Cc escapes its natural mitochondrial environment and, once in the cytosol, it binds other proteins to form a complex named the apoptosome—a platform that triggers caspase activation and further leads to controlled cell dismantlement. Early released Cc also binds to inositol 1,4,5‐triphosphate receptors on the ER membrane, which stimulates further massive Cc release from mitochondria. Besides the well‐characterized binding proteins contributing to the proapoptotic functions of Cc, many novel protein targets have been recently described. Among them, histone chaperones were identified as key partners of Cc following DNA breaks, indicating that Cc might modulate chromatin dynamics through competitive binding to histone chaperones. In this article, we review the ample set of recently discovered antiapoptotic proteins—involved in DNA damage, transcription, and energetic metabolism—reported to interact with Cc in the cytoplasm and even the nucleus upon DNA breaks.

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Section: Cytochrome C In the Cytoplasm: Established And New Targetsmentioning

confidence: 99%

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

et al. 2019

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“…14-3-3ζ is a member of the 14-3-3 scaffold protein family, which are highly conserved serine and threonine binding proteins present in all eukaryotes [ [16] , [17] , [18] , [19] ]. They bind to a diverse number of enzymes, signaling proteins, and transcription factors and have been implicated in the regulation of numerous cellular processes, including proliferation, protein trafficking, and apoptosis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

14-3-3ζ mediates an alternative, non-thermogenic mechanism in male mice to reduce heat loss and improve cold tolerance

Diallo

Dussault

Noll

et al. 2020

Molecular Metabolism

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Objective Adaptive thermogenesis, which is partly mediated by sympathetic input on brown adipose tissue (BAT), is a mechanism of heat production that confers protection against prolonged cold exposure. Various endogenous stimuli, for example, norepinephrine and FGF-21, can also promote the conversion of inguinal white adipocytes to beige adipocytes, which may represent a secondary cell type that contributes to adaptive thermogenesis. We previously identified an essential role of the molecular scaffold 14-3-3ζ in adipogenesis, but one of the earliest, identified functions of 14-3-3ζ is its regulatory effects on the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of norepinephrine. Herein, we examined whether 14-3-3ζ could influence adaptive thermogenesis via actions on BAT activation or the beiging of white adipocytes. Methods Transgenic mice over-expressing a TAP-tagged human 14-3-3ζ molecule or heterozygous mice without one allele of Ywhaz , the gene encoding 14-3-3ζ, were used to explore the contribution of 14-3-3ζ to acute (3 h) and prolonged (3 days) cold (4 °C) exposure. Metabolic caging experiments, PET-CT imaging, and laser Doppler imaging were used to determine the effect of 14-3-3ζ over-expression on thermogenic and vasoconstrictive mechanisms in response to cold. Results Transgenic over-expression of 14-3-3ζ (TAP) in male mice significantly improved tolerance to acute and prolonged cold. In response to cold, body temperatures in TAP mice did not decrease to the same extent when compared to wildtype (WT) mice, and this was associated with increased UCP1 expression in beige inguinal white tissue (iWAT) and BAT. Of note was the paradoxical finding that cold-induced changes in body temperatures of TAP mice were associated with significantly decreased energy expenditure. The marked improvements in tolerance to prolonged cold were not due to changes in sensitivity to β-adrenergic stimulation or BAT or iWAT oxidative metabolism; instead, over-expression of 14-3-3ζ significantly decreased thermal conductance and heat loss in mice via increased peripheral vasoconstriction. Conclusions Despite being associated with elevations in cold-induced UCP1 expression in brown or beige adipocytes, these findings suggest that 14-3-3ζ regulates an alternative, non-thermogenic mechanism via vasoconstriction to minimize heat loss during cold exposure.

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“…The 14-3-3 protein family is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs) [8]. Previous many evidences show that misregulation of 14-3-3 proteins contributes to important human diseases such as cancer, neurodegenerative disorders, and infection by Giardia intestinalis [12][13][14][15].However, Current studies have found that the 14-3-3 protein family subtypes interact with target proteins to participate in the pathogenesis of varieties of autoimmune disease including rheumatoid arthritis, systemic sclerosis, and large vessel vasculitis [16][17][18]. Furthermore, Li et al [19] found that upregulating 14-3-3σ can enhance IgE class switching and antibody secretion of B cells in asthma model of miR146a overexpressing mice, which increases in IgE are linked with worsened asthma severity.…”

Section: Introductionmentioning

confidence: 99%

Serum 14-3-3β Protein: a New Biomarker in Asthmatic Patients With Acute Attack

Wang

Rao

Cui

et al. 2021

Preprint

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Background: The determination of systemic inflammatory markers is one of the important directions to study the pathogenesis of asthma and improve the diagnosis of asthma. Current studies have found that the 14-3-3 protein family subtypes interact with target proteins to participate in the pathogenesis of a variety of immune inflammatory diseases. However, studies on serum tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein β (14-3-3β) in asthma are scarce. This study aimed to assess the clinical significance of 14-3-3β in asthmatic patients. Methods: We recruited 54 asthmatic patients with acute attack and 50 asthmatic patients with chronic persistent. The normal control group included 54 healthy individuals with similar sex-age indicators. Clinical characteristics (age, gender, height and weight), clinical indicators [fractional expiratory nitric oxide (FeNO), eosinophil count, forced vital capacity (FVC), percent of predicted FVC (FVC % predicted), forced expiratory volume in one second (FEV1), percent of predicted FEV1 (FEV1% predicted), the ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and percent of predicted FEV1/FVC (FEV1/FVC% predicted)] and serum 14-3-3β levels were measured to compare among each group. Spearman’s rank correlation coefficient was used to evaluate the correlation between 14-3-3β and clinical indicators. Finally, Receiver-operating characteristic (ROC) curves analysis was used to determine the sensitivity and specificity of 14-3-3β.Results: Our results showed that median (interquartile range) of serum 14-3-3β concentration (ng/ml) in acute attack group of asthma (41.18 [33.06-51.76]) was much higher than that in normal control group (24.99 [17.43-29.91]; P<0.001) and chronic persistent group of asthma (25.88 [21.03-34.55]; P<0.001),however, it was that exist no statistical heterogeneity with regard to the serum 14-3-3β level between the chronic persistent group of asthma and the healthy individuals (P >0.05). Spearman’s correlation coefficient shows that the serum 14-3-3β level was positively correlated with FeNO (r=-0.292, P=0.032) and peripheral blood eosinophil count (r=0.328, P=0.016), and was negatively related to FEV1/FVC (r=-0.293, P=0.031) and FEV1/FVC% predicted (r=-0.299, P=0.028) in the acute attack group of asthma. At the same time, the serum 14-3-3β level was also negatively associated with FEV1 (r=-0.297, P=0.036) in the chronic persistent group of asthma. ROC curve analysis comparing acute attack group of asthma with normal control group demonstrated a significant (P<0.001) AUC of 0.90 (95% CI, 0.85–0.96). When the cut off value was 29.70 ng/ml, the ROC curve yielded a sensitivity of 92.6%, a specificity of 75.9%, a positive likelihood ratio (+LR) of 3.84, negative likelihood ratio (-LR) of 0.10 and a Youden index of 0.69 in acute attack group of asthma. ROC curve analysis comparing chronic persistent group of asthma with normal control group demonstrated no statistically significant difference (P>0.05) AUC of 0.60 (95% CI, 0.49–0.70). Conclusion: The Elevated serum 14-3-3β levels may be associated with airway inflammation and impaired bronchial patency in the acute attack of asthma. The serum 14-3-3β protein can be used to distinguish between asthmatic patients with acute attack and healthy individuals and may become a potential biomarker in asthmatic patients with acute attack.

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Can 14-3-3 proteins serve as therapeutic targets for the treatment of metabolic diseases?

Cited by 32 publications

References 137 publications

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

14-3-3ζ mediates an alternative, non-thermogenic mechanism in male mice to reduce heat loss and improve cold tolerance

Serum 14-3-3β Protein: a New Biomarker in Asthmatic Patients With Acute Attack

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