Physiological function of FKBP12, a primary target of rapamycin/FK506: a newly identified role in transcription of ribosomal protein genes in yeast

Koyamada, Koji

doi:10.1007/s00294-020-01142-3

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…Rapamycin, a calcineurin inhibitor, similar to cyclosporine A (CsA) and FK506, has been widely used in preventing allograft rejection [ 23 ]. It exerts an effect by binding to the intracellular immunophilin FK506 binding protein (FKBP12) [ 24 ]. However, unlike CsA and FK506, the rapamycin-FKBP12 complex inhibits the function of mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation and inhibits the cell cycle [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

Zhen¹,

Li²,

Mu³

et al. 2022

Mediators of Inflammation

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Background. Recent genetic studies indicated that variants of autophagy genes were associated with the predisposition of Crohn’s disease (CD). The autophagy deficiency may affect the innate and adaptive immunity, which is related to persistent and excessive inflammation of the bowel. However, it remains unclear how autophagy modulates the expression of immune response regulator NF-κB and proinflammatory cytokine TNF-α in CD. Aim. We aimed to investigate the role of rapamycin on the expression of NF-κB p65 and TNF-α in 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis and lipopolysaccharide (LPS)-induced HT-29 cells. Methods. TNBS-induced colitis mice were treated with saline or rapamycin, and the disease activity index (DAI) and histological scores of colonic mucosa were evaluated. The expressions of p65, ATG16L1 and LC3 were detected by western blot and immunohistochemistry staining. The monodansylcadaverine (MDC) staining and transmission electron microscopy were developed to study the autophagy in LPS-induced HT-29 cells. Expression of TNF-α from colon tissue and HT-29 cells were detected by ELISA. The expressions of p65, ATG16L1 and LC3 in active CD patients were also investigated. Results. Significantly more autophagosomes were observed in rapamycin-treated cells than in controls. Rapamycin remarkably upregulated the expression of ATG16L1 and LC3II, inhibited p65 nucleus translocation and secretion of TNF-α both in vivo and in vitro. The expression of both ATG16L1 and LC3II increased in mild to moderate CD specimens, while no significant difference was noted between severe CD and normal controls. The expression of p65 increased notably in severe CD compared to those in mild to moderate patients. Conclusions. In LPS-treated HT-29 cells and TNBS-induced colitis, p65 is overexpressed, which results in exaggerated secretion of TNF-α and induce or worsen the inflammation in the bowel. Rapamycin protects against colitis through induction of autophagy, thus inhibiting the activation of NF-κB pathway and secretion of TNF-α.

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Section: Discussionmentioning

confidence: 99%

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

Zhen¹,

Li²,

Mu³

et al. 2022

Mediators of Inflammation

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“…Inside the cell, rapamycin first forms a gain-of-function complex with FKBP12, the well-known rapamycin cellular receptor [14,19,20], which then inhibits the TOR kinases. Currently, FKBP12 has been well studied in both S. cerevisiae [22,57,58] and human cell Fig. 5 Fold change of DEGs related to cellulose degradation that are categorized into four types: a cellulase; b nonenzymatic cellulose attacking enzymes; c hemicellulase, and d transcriptional factors [59][60][61].…”

Section: Fkbp12 Is Required For the Temporary Inhibition Of Rapamycinmentioning

confidence: 99%

High-dose rapamycin exerts a temporary impact on T. reesei RUT-C30 through gene trFKBP12

Pang

Wang

Zhang

et al. 2021

Biotechnol Biofuels

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Background Knowledge with respect to regulatory systems for cellulase production is prerequisite for exploitation of such regulatory networks to increase cellulase production, improve fermentation efficiency and reduce the relevant production cost. The target of rapamycin (TOR) signaling pathway is considered as a central signaling hub coordinating eukaryotic cell growth and metabolism with environmental inputs. However, how and to what extent the TOR signaling pathway and rapamycin are involved in cellulase production remain elusive. Result At the early fermentation stage, high-dose rapamycin (100 μM) caused a temporary inhibition effect on cellulase production, cell growth and sporulation of Trichoderma reesei RUT-C30 independently of the carbon sources, and specifically caused a tentative morphology defect in RUT-C30 grown on cellulose. On the contrary, the lipid content of T. reesei RUT-C30 was not affected by rapamycin. Accordingly, the transcriptional levels of genes involved in the cellulase production were downregulated notably with the addition of rapamycin. Although the mRNA levels of the putative rapamycin receptor trFKBP12 was upregulated significantly by rapamycin, gene trTOR (the downstream effector of the rapamycin–FKBP12 complex) and genes associated with the TOR signaling pathways were not changed markedly. With the deletion of gene trFKBP12, there is no impact of rapamycin on cellulase production, indicating that trFKBP12 mediates the observed temporary inhibition effect of rapamycin. Conclusion Our study shows for the first time that only high-concentration rapamycin induced a transient impact on T. reesei RUT-C30 at its early cultivation stage, demonstrating T. reesei RUT-C30 is highly resistant to rapamycin, probably due to that trTOR and its related signaling pathways were not that sensitive to rapamycin. This temporary influence of rapamycin was facilitated by gene trFKBP12. These findings add to our knowledge on the roles of rapamycin and the TOR signaling pathways play in T. reesei.

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“…FK506-binding protein 12 (FKBP12) is another immunophilin being a primary target for two structurally related drugs, FK506 and rapamycin 72 . Binding of FKBP12 with FK506 inhibits bone morphogenetic proteins (BMPs)-related signaling pathway 73 .…”

Section: Roles Of Cypa In Kidney Diseasesmentioning

confidence: 99%

Current update on theranostic roles of cyclophilin A in kidney diseases

Hadpech¹,

Thongboonkerd²

2022

Theranostics

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Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.

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Physiological function of FKBP12, a primary target of rapamycin/FK506: a newly identified role in transcription of ribosomal protein genes in yeast

Cited by 15 publications

References 40 publications

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

High-dose rapamycin exerts a temporary impact on T. reesei RUT-C30 through gene trFKBP12

Current update on theranostic roles of cyclophilin A in kidney diseases

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