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Your search keyword '"Villella, Valeria R."' showing total 6 results
Start Over Author "Villella, Valeria R." Topic proteostasis
6 results on '"Villella, Valeria R."'

1. Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.

Author

van de Veerdonk FL, Renga G, Pariano M, Bellet MM, Servillo G, Fallarino F, De Luca A, Iannitti RG, Piobbico D, Gargaro M, Manni G, D'Onofrio F, Stincardini C, Sforna L, Borghi M, Castelli M, Pieroni S, Oikonomou V, Villella VR, Puccetti M, Giovagnoli S, Galarini R, Barola C, Maiuri L, Della Fazia MA, Cellini B, Talesa VN, Dinarello CA, Costantini C, and Romani L

Subjects
Animals, Female, Male, Mice, Mice, Knockout, Oxidation-Reduction drug effects, Autophagy drug effects, Interleukin 1 Receptor Antagonist Protein pharmacology, Mitochondria metabolism, Oxidative Stress drug effects, Proteostasis drug effects
Abstract

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1-dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

Published
2022
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2. Defective proteostasis in celiac disease as a new therapeutic target.

Author

Maiuri L, Villella VR, Piacentini M, Raia V, and Kroemer G

Subjects
Humans, Celiac Disease genetics, Proteostasis genetics
Abstract

Cystic fibrosis (CF) is a disease caused by loss-of-function mutations affecting the CF transmembrane conductance regulator (CFTR), a chloride channel. Recent evidence indicates that CFTR is inhibited by a gluten/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an "infernal trio". The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten/gliadin-derived peptide (P57-68), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57-68) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the "infernal trio" including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy.

Published
2019
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4. Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

Author

van de Veerdonk, Frank L, Renga, Giorgia, Pariano, Marilena, Bellet, Marina M, Servillo, Giuseppe, Fallarino, Francesca, De Luca, Antonella, Iannitti, Rossana G, Piobbico, Danilo, Gargaro, Marco, Manni, Giorgia, D'Onofrio, Fiorella, Stincardini, Claudia, Sforna, Luigi, Borghi, Monica, Castelli, Marilena, Pieroni, Stefania, Oikonomou, Vasileios, Villella, Valeria R, Puccetti, Matteo, Giovagnoli, Stefano, Galarini, Roberta, Barola, Carolina, Maiuri, Luigi, Della Fazia, Maria Agnese, Cellini, Barbara, Talesa, Vincenzo Nicola, Dinarello, Charles A, Costantini, Claudio, Romani, Luigina, van de Veerdonk, Frank L, Renga, Giorgia, Pariano, Marilena, Bellet, Marina M, Servillo, Giuseppe, Fallarino, Francesca, De Luca, Antonella, Iannitti, Rossana G, Piobbico, Danilo, Gargaro, Marco, Manni, Giorgia, D'Onofrio, Fiorella, Stincardini, Claudia, Sforna, Luigi, Borghi, Monica, Castelli, Marilena, Pieroni, Stefania, Oikonomou, Vasileio, Villella, Valeria R, Puccetti, Matteo, Giovagnoli, Stefano, Galarini, Roberta, Barola, Carolina, Maiuri, Luigi, Della Fazia, Maria Agnese, Cellini, Barbara, Talesa, Vincenzo Nicola, Dinarello, Charles A, Costantini, Claudio, and Romani, Luigina

Subjects
Fungal infection, Male, medicine.drug_class, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], medicine.disease_cause, Mice, Fungal infections, All institutes and research themes of the Radboud University Medical Center, medicine, Autophagy, Animals, Receptor, Mice, Knockout, Inflammation, Anakinra, Infectious disease, NADPH oxidase, biology, Chemistry, General Medicine, Aryl hydrocarbon receptor, Receptor antagonist, Cell biology, Mitochondria, Interleukin 1 Receptor Antagonist Protein, Oxidative Stress, Proteostasis, biology.protein, Female, Oxidation-Reduction, Oxidative stress, medicine.drug, Research Article
Abstract

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

Published
2022

6. Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis

Author

Guido Kroemer, Luigi Maiuri, Valeria Raia, Valeria Rachela Villella, Antonella Tosco, Speranza Esposito, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Department of Pediatrics, Regional Cystic Fibrosis Center, Medicine School, University 'Federico II', Université Pierre et Marie Curie - Paris 6 (UPMC), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Department of Women's and Children's Health, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], SCDU of Pediatrics, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi del Piemonte Orientale-Amedeo Avogadro (ITALY), Esposito, Speranza, Tosco, Antonella, Villella, Valeria R, Raia, Valeria, Kroemer, Guido, Maiuri, Luigi, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), University of Piemonte Orientale, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Mini Review, medicine.disease_cause, Cystic fibrosis, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, medicine, Autophagy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CFTR, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Mutation, biology, business.industry, Potentiator, respiratory system, medicine.disease, Cystic fibrosis transmembrane conductance regulator, 3. Good health, respiratory tract diseases, 030104 developmental biology, Proteostasis, Cystic fibrosi, 030220 oncology & carcinogenesis, Immunology, Chloride channel, Cancer research, biology.protein, business, CFTR-repairing therapy, medicine.drug
Abstract

International audience; Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

Published
2016

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