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  1. Article ; Online: The FKBP51 Glucocorticoid Receptor Co-Chaperone

    Gabriel R. Fries / Nils C. Gassen / Theo Rein

    International Journal of Molecular Sciences, Vol 18, Iss 12, p

    Regulation, Function, and Implications in Health and Disease

    2017  Volume 2614

    Abstract: Among the chaperones and co-chaperones regulating the glucocorticoid receptor (GR), FK506 binding protein (FKBP) 51 is the most intensely investigated across different disciplines. This review provides an update on the role of the different co-chaperones ...

    Abstract Among the chaperones and co-chaperones regulating the glucocorticoid receptor (GR), FK506 binding protein (FKBP) 51 is the most intensely investigated across different disciplines. This review provides an update on the role of the different co-chaperones of Hsp70 and Hsp90 in the regulation of GR function. The development leading to the focus on FKBP51 is outlined. Further, a survey of the vast literature on the mechanism and function of FKBP51 is provided. This includes its structure and biochemical function, its regulation on different levels—transcription, post-transcription, and post-translation—and its function in signaling pathways. The evidence portraying FKBP51 as a scaffolding protein organizing protein complexes rather than a chaperone contributing to the folding of individual proteins is collated. Finally, FKBP51’s involvement in physiology and disease is outlined, and the promising efforts in developing drugs targeting FKBP51 are discussed.
    Keywords chaperone ; glucocorticoid receptor ; FKBP51 ; FKBP5 ; signaling pathway ; drug ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 570
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Focus on FKBP51

    Alexander S. Häusl / Georgia Balsevich / Nils C. Gassen / Mathias V. Schmidt

    Molecular Metabolism, Vol 29, Iss , Pp 170-

    A molecular link between stress and metabolic disorders

    2019  Volume 181

    Abstract: Background: Obesity, Type 2 diabetes (T2D) as well as stress-related disorders are rising public health threats and major burdens for modern society. Chronic stress and depression are highly associated with symptoms of the metabolic syndrome, but the ... ...

    Abstract Background: Obesity, Type 2 diabetes (T2D) as well as stress-related disorders are rising public health threats and major burdens for modern society. Chronic stress and depression are highly associated with symptoms of the metabolic syndrome, but the molecular link is still not fully understood. Furthermore, therapies tackling these biological disorders are still lacking. The identification of shared molecular targets underlying both pathophysiologies may lead to the development of new treatments. The FK506 binding protein 51 (FKBP51) has recently been identified as a promising therapeutic target for stress-related psychiatric disorders and obesity-related metabolic outcomes. Scope of the review: The aim of this review is to summarize current evidence of in vitro, preclinical, and human studies on the stress responsive protein FKBP51, focusing on its newly discovered role in metabolism. Also, we highlight the therapeutic potential of FKBP51 as a new treatment target for symptoms of the metabolic syndrome. Major conclusions: We conclude the review by emphasizing missing knowledge gaps that remain and future research opportunities needed to implement FKBP51 as a drug target for stress-related obesity or T2D. Keywords: FKBP51, SAFit2, Adipogensis, Glucose uptake, Obesity, Stress, Type 2 diabetes
    Keywords Internal medicine ; RC31-1245
    Subject code 150
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

    Silvia Martinelli / Elmira A. Anderzhanova / Thomas Bajaj / Svenja Wiechmann / Frederik Dethloff / Katja Weckmann / Daniel E. Heinz / Tim Ebert / Jakob Hartmann / Thomas M. Geiger / Michael Döngi / Kathrin Hafner / Max L. Pöhlmann / Lee Jollans / Alexandra Philipsen / Susanne V. Schmidt / Ulrike Schmidt / Giuseppina Maccarrone / Valentin Stein /
    Felix Hausch / Christoph W. Turck / Mathias V. Schmidt / Anne-Kathrin Gellner / Bernhard Kuster / Nils C. Gassen

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor ... ...

    Abstract Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor processing and potentially altering adult synaptic plasticity.
    Keywords Science ; Q
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

    Nils C. Gassen / Jan Papies / Thomas Bajaj / Jackson Emanuel / Frederik Dethloff / Robert Lorenz Chua / Jakob Trimpert / Nicolas Heinemann / Christine Niemeyer / Friderike Weege / Katja Hönzke / Tom Aschman / Daniel E. Heinz / Katja Weckmann / Tim Ebert / Andreas Zellner / Martina Lennarz / Emanuel Wyler / Simon Schroeder /
    Anja Richter / Daniela Niemeyer / Karen Hoffmann / Thomas F. Meyer / Frank L. Heppner / Victor M. Corman / Markus Landthaler / Andreas C. Hocke / Markus Morkel / Nikolaus Osterrieder / Christian Conrad / Roland Eils / Helena Radbruch / Patrick Giavalisco / Christian Drosten / Marcel A. Müller

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Viruses manipulate host cell pathways to support infection. Here the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition. ...

    Abstract Viruses manipulate host cell pathways to support infection. Here the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition.
    Keywords Science ; Q
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection

    Nils C. Gassen / Daniela Niemeyer / Doreen Muth / Victor M. Corman / Silvia Martinelli / Alwine Gassen / Kathrin Hafner / Jan Papies / Kirstin Mösbauer / Andreas Zellner / Anthony S. Zannas / Alexander Herrmann / Florian Holsboer / Ruth Brack-Werner / Michael Boshart / Bertram Müller-Myhsok / Christian Drosten / Marcel A. Müller / Theo Rein

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 16

    Abstract: Here, Gassen et al. show that S-phase kinase-associated protein 2 (SKP2) is responsible for lysine-48-linked poly-ubiquitination of beclin 1, resulting in its proteasomal degradation, and that inhibition of SKP2 enhances autophagy and reduces replication ...

    Abstract Here, Gassen et al. show that S-phase kinase-associated protein 2 (SKP2) is responsible for lysine-48-linked poly-ubiquitination of beclin 1, resulting in its proteasomal degradation, and that inhibition of SKP2 enhances autophagy and reduces replication of MERS coronavirus.
    Keywords Science ; Q
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function.

    Regina T Knapp / Michael J H Wong / Lorenz K Kollmannsberger / Nils C Gassen / Anja Kretzschmar / Jürgen Zschocke / Kathrin Hafner / Jason C Young / Theo Rein

    PLoS ONE, Vol 9, Iss 1, p e

    2014  Volume 85415

    Abstract: Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing ... ...

    Abstract Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the androgen receptor (AR). BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function

    Georgia Balsevich / Alexander S. Häusl / Carola W. Meyer / Stoyo Karamihalev / Xixi Feng / Max L. Pöhlmann / Carine Dournes / Andres Uribe-Marino / Sara Santarelli / Christiana Labermaier / Kathrin Hafner / Tianqi Mao / Michaela Breitsamer / Marily Theodoropoulou / Christian Namendorf / Manfred Uhr / Marcelo Paez-Pereda / Gerhard Winter / Felix Hausch /
    Alon Chen / Matthias H. Tschöp / Theo Rein / Nils C. Gassen / Mathias V. Schmidt

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 12

    Abstract: Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression ... ...

    Abstract Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function

    Georgia Balsevich / Alexander S. Häusl / Carola W. Meyer / Stoyo Karamihalev / Xixi Feng / Max L. Pöhlmann / Carine Dournes / Andres Uribe-Marino / Sara Santarelli / Christiana Labermaier / Kathrin Hafner / Tianqi Mao / Michaela Breitsamer / Marily Theodoropoulou / Christian Namendorf / Manfred Uhr / Marcelo Paez-Pereda / Gerhard Winter / Felix Hausch /
    Alon Chen / Matthias H. Tschöp / Theo Rein / Nils C. Gassen / Mathias V. Schmidt

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 12

    Abstract: Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression ... ...

    Abstract Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.
    Keywords Science ; Q
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response

    Nils C Gassen / Jakob Hartmann / Jürgen Zschocke / Jens Stepan / Kathrin Hafner / Andreas Zellner / Thomas Kirmeier / Lorenz Kollmannsberger / Klaus V Wagner / Nina Dedic / Georgia Balsevich / Jan M Deussing / Stefan Kloiber / Susanne Lucae / Florian Holsboer / Matthias Eder / Manfred Uhr / Marcus Ising / Mathias V Schmidt /
    Theo Rein

    PLoS Medicine, Vol 11, Iss 11, p e

    evidence in cells, mice, and humans.

    2014  Volume 1001755

    Abstract: FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, ...

    Abstract FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, the underlying mechanisms remain elusive. The objective of this study was to elucidate the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy.Established cell lines, primary neural cells, human blood cells of healthy individuals and patients with depression, and mice were treated with antidepressants. Mice were tested for several neuroendocrine and behavioral parameters. Protein interactions and autophagic pathway activity were mainly evaluated by co-immunoprecipitation and Western blots. We first show that the effects of acute antidepressant treatment on behavior are abolished in FKBP51 knockout (51KO) mice. Autophagic markers, such as the autophagy initiator Beclin1, were increased following acute antidepressant treatment in brains from wild-type, but not 51KO, animals. FKBP51 binds to Beclin1, changes decisive protein interactions and phosphorylation of Beclin1, and triggers autophagic pathways. Antidepressants and FKBP51 exhibited synergistic effects on these pathways. Using chronic social defeat as a depression-relevant stress model in combination with chronic paroxetine (PAR) treatment revealed that the stress response, as well as the effects of antidepressants on behavior and autophagic markers, depends on FKBP51. In human blood cells of healthy individuals, FKBP51 levels correlated with the potential of antidepressants to induce autophagic pathways. Importantly, the clinical antidepressant response of patients with depression (n = 51) could be predicted by the antidepressant response of autophagic markers in patient-derived peripheral blood lymphocytes cultivated and treated ex vivo (Beclin1/amitriptyline: r = 0.572, p = 0.003; Beclin1/PAR: r = 0.569, p = 0.004; Beclin1/fluoxetine: r = 0.454, p = 0.026; ...
    Keywords Medicine ; R
    Subject code 616
    Language English
    Publishing date 2014-11-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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