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Effects of peptidyl-prolyl isomerase 1 depletion in animal models of prion diseases.

ABSTRACT: Pin1 is a peptidyl-prolyl isomerase that induces the cis-trans conversion of specific Ser/Thr-Pro peptide bonds in phosphorylated proteins, leading to conformational changes through which Pin1 regulates protein stability and activity. Since down-regulation of Pin1 has been described in several neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD), we investigated its potential role in prion diseases. Animals generated on wild-type (Pin1+/+), hemizygous (Pin1+/-) or knock-out (Pin1-/-) background for Pin1 were experimentally infected with RML prions. The study indicates that, neither the total depletion nor reduced levels of Pin1 significantly altered the clinical and neuropathological features of the disease.

SUBMITTER: Legname G

PROVIDER: S-EPMC6016513 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Effects of peptidyl-prolyl isomerase 1 depletion in animal models of prion diseases.

Legname Giuseppe G Virgilio Tommaso T Bistaffa Edoardo E De Luca Chiara Maria Giulia CMG Catania Marcella M Zago Paola P Isopi Elisa E Campagnani Ilaria I Tagliavini Fabrizio F Giaccone Giorgio G Moda Fabio F

Prion 20180301 2

Pin1 is a peptidyl-prolyl isomerase that induces the cis-trans conversion of specific Ser/Thr-Pro peptide bonds in phosphorylated proteins, leading to conformational changes through which Pin1 regulates protein stability and activity. Since down-regulation of Pin1 has been described in several neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD), we investigated its potential role in prion diseases. Animals generated on wild-type ...[more]

PMID: 29676205

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Kinetic isotope effects support the twisted amide mechanism of Pin1 peptidyl-prolyl isomerase.

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Functional Analysis of Peptidyl-prolyl cis-trans Isomerase from Aspergillus flavus.

Project description:Aspergillus flavus, a ubiquitous filamentous fungus found in soil, plants and other substrates has been reported not only as a pathogen for plants, but also a carcinogen producing fungus for human. Peptidyl-Prolyl Isomerase (PPIases) plays an important role in cell process such as protein secretion cell cycle control and RNA processing. However, the function of PPIase has not yet been identified in A. flavus. In this study, the PPIases gene from A. flavus named ppci1 was cloned into expression vector and the protein was expressed in prokaryotic expression system. Activity of recombinant ppci1 protein was particularly inhibited by FK506, CsA and rapamycin. 3D-Homology model of ppci1 has been constructed with the template, based on 59.7% amino acid similarity. The homologous recombination method was used to construct the single ppci1 gene deletion strain Δppci1. We found that, the ppci1 gene plays important roles in A. flavus growth, conidiation, and sclerotia formation, all of which showed reduction in Δppci1 and increased in conidiation compared with the wild-type and complementary strains in A. flavus. Furthermore, aflatoxin and peanut seeds infection assays indicated that ppci1 contributes to virulence of A. flavus. Furthermore, we evaluated the effect of PPIase inhibitors on A. flavus growth, whereby these were used to treat wild-type strains. We found that the growths were inhibited under every inhibitor. All, these results may provide valuable information for designing inhibitors in the controlling infections of A. flavus.

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Pathologic role of peptidyl-prolyl isomerase Pin1 in pulmonary artery remodeling.

Project description:Peptidyl-prolyl isomerase Pin1 is crucial for cell proliferation, but its role in pulmonary artery remodeling (PAR) is unclear. In the present study, we aimed to evaluate the expression and contribution of Pin1 in PAR. Treatment with Pin1 inhibitor Juglone or Pin1-specific siRNAs ameliorated the expression of Pin1 and proliferating cell nuclear antigen (PCNA) in human pulmonary artery smooth muscle cells (PASMCs) in vitro, and Juglone treatment arrested the cell cycle at the G1 phase. Treatment with transforming growth factor β1 (TGF-β1) also enhanced Pin1 expression and PASMC proliferation. Immunohistochemical staining revealed that Pin1 and PCNA expression levels were increased and positively correlated with each other in PAR samples from humans and monocrotaline-treated Sprague-Dawley rats; these proteins were mainly localized in arteries undergoing remodeling, as well as inflammatory cells, and hyperplastic bronchial epithelial cells. Intraperitoneal injection of Juglone also led to morphologic and hemodynamic changes in PAR rats. Additionally, PAR rats displayed higher serum and lung TGF-β1 levels compared with controls, while administration of Juglone to PAR rats suppressed serum and lung TGF-β1 levels. The findings in this study suggest that TGF-β1 and Pin1 constitute a positive feedback loop, which plays an important role in the pathophysiology of PAR.

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Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase.

Project description:The peptidyl-prolyl isomerase Pin1 cooperates with proline-directed kinases and phosphatases to regulate multiple oncogenic pathways. Pin1 specifically recognizes phosphorylated Ser/Thr-Pro motifs in proteins and catalyzes their cis-trans isomerization. The Pin1-catalyzed conformational changes determine the stability, activity, and subcellular localization of numerous protein substrates. We conducted a survey of eukaryotic protein kinases that are regulated by Pin1 and whose Pin1 binding sites have been identified. Our analyses reveal that Pin1 target sites in kinases do not fall exclusively within the intrinsically disordered regions of these enzymes. Rather, they fall into three groups based on their location: (i) within the catalytic kinase domain, (ii) in the C-terminal kinase region, and (iii) in regulatory domains. Some of the kinases downregulated by Pin1 activity are tumor-suppressing, and all kinases upregulated by Pin1 activity are functionally pro-oncogenic. These findings further reinforce the rationale for developing Pin1-specific inhibitors as attractive pharmaceuticals for cancer therapy.

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Project description:Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3' UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with Pin1 being a PTH mRNA destabilizing protein. Initial analysis indicated that Pin1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of Pin1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. Pin1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, Pin1 inhibition decreased KSRP-PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, Pin1-/- mice displayed increased serum PTH and PTH mRNA levels, suggesting that Pin1 determines basal PTH expression in vivo. These results demonstrate that Pin1 is a key mediator of PTH mRNA stability and indicate a role for Pin1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.

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Cellular peptidyl-prolyl cis/trans isomerase Pin1 facilitates replication of feline coronavirus.

Project description:Although feline coronavirus (FCoV) causes feline infectious peritonitis (FIP), which is a fatal infectious disease, there are no effective therapeutic medicines or vaccines. Previously, in vitro studies have shown that cyclosporin (CsA) and FK506 inhibit virus replication in diverse coronaviruses. CsA and FK506 are targets of clinically relevant immunosuppressive drugs and bind to cellular cyclophilins (Cyps) or FK506 binding proteins (FKBPs), respectively. Both Cyp and FKBP have peptidyl-prolyl cis-trans isomerase (PPIase) activity. However, protein interacting with NIMA (Pin1), a member of the parvulin subfamily of PPIases that differs from Cyps and FKBPs, is essential for various signaling pathways. Here we demonstrated that genetic silencing or knockout of Pin1 resulted in decreased FCoV replication in vitro. Dipentamethylene thiuram monosulfide, a specific inhibitor of Pin1, inhibited FCoV replication. These data indicate that Pin1 modulates FCoV propagation.

| S-EPMC7113879 | biostudies-literature

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