@article{MTMT:34108329, title = {The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer's Disease}, url = {https://m2.mtmt.hu/api/publication/34108329}, author = {Roe, S. Mark and Török, Zsolt and McGown, Andrew and Horváth, Ibolya and Spencer, John and Pazmany, Tamas and Vigh, László and Prodromou, Chrisostomos}, doi = {10.3390/biom13071051}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {13}, unique-id = {34108329}, issn = {2218-273X}, abstract = {Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer's disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-& beta; (A & beta;) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen.}, keywords = {DEPHOSPHORYLATION; MODEL; TAU; Alzheimer's disease; A-BETA; HSP90; HSP90; chaperone; Co-chaperone; Amyloid hypothesis; FKBP51; FKBP52; Cochaperone; immunopilin; LA1011; TAU FORMS}, year = {2023}, eissn = {2218-273X}, orcid-numbers = {McGown, Andrew/0000-0002-2187-3850} } @article{MTMT:32849807, title = {Distinct Cellular Tools of Mild Hyperthermia-Induced Acquired Stress Tolerance in Chinese Hamster Ovary Cells.}, url = {https://m2.mtmt.hu/api/publication/32849807}, author = {Tiszlavicz, Ádám and Gombos, Imre and Péter, Mária and Hegedűs, Zoltán and Hunya, Ákos and Dukic, Barbara and Nagy, István and Peksel, Begüm and Balogh, Gábor and Horváth, Ibolya and Vigh, László and Török, Zsolt}, doi = {10.3390/biomedicines10051172}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {10}, unique-id = {32849807}, abstract = {Mild stress could help cells to survive more severe environmental or pathophysiological conditions. In the current study, we investigated the cellular mechanisms which contribute to the development of stress tolerance upon a prolonged (0-12 h) fever-like (40 °C) or a moderate (42.5 °C) hyperthermia in mammalian Chinese Hamster Ovary (CHO) cells. Our results indicate that mild heat triggers a distinct, dose-dependent remodeling of the cellular lipidome followed by the expression of heat shock proteins only at higher heat dosages. A significant elevation in the relative concentration of saturated membrane lipid species and specific lysophosphatidylinositol and sphingolipid species suggests prompt membrane microdomain reorganization and an overall membrane rigidification in response to the fluidizing heat in a time-dependent manner. RNAseq experiments reveal that mild heat initiates endoplasmic reticulum stress-related signaling cascades resulting in lipid rearrangement and ultimately in an elevated resistance against membrane fluidization by benzyl alcohol. To protect cells against lethal, protein-denaturing high temperatures, the classical heat shock protein response was required. The different layers of stress response elicited by different heat dosages highlight the capability of cells to utilize multiple tools to gain resistance against or to survive lethal stress conditions.}, keywords = {MEMBRANE; STRESS; heat shock response; transcriptomics; LIPIDOMICS; Unfolded protein response; Chinese hamster ovary cells; acquired stress tolerance; membrane lipid metabolism}, year = {2022}, eissn = {2227-9059}, orcid-numbers = {Hunya, Ákos/0000-0002-4547-9284} } @article{MTMT:32058440, title = {Silencing of Poly(ADP-Ribose) Polymerase-2 Induces Mitochondrial Reactive Species Production and Mitochondrial Fragmentation}, url = {https://m2.mtmt.hu/api/publication/32058440}, author = {Jankó, Laura and Kovács, Tünde and Laczik, Miklós and Sári, Zsanett Mercédesz and Ujlaki, Gyula and Kis, Nikoletta Gréta and Horváth, Ibolya and Antal, Miklós and Vigh, László and Bálint, Bálint László and Uray (Davis), Karen L. and Bay, Péter}, doi = {10.3390/cells10061387}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {10}, unique-id = {32058440}, year = {2021}, eissn = {2073-4409}, orcid-numbers = {Bálint, Bálint László/0000-0002-6163-7190; Uray (Davis), Karen L./0000-0001-6997-459X; Bay, Péter/0000-0002-6191-6616} } @article{MTMT:30431480, title = {The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization}, url = {https://m2.mtmt.hu/api/publication/30431480}, author = {Szabó, Írisz and M.Tóth, Orsolya and Török, Zsolt and Varga, Dániel Péter and Menyhárt, Ákos and Frank, Rita and Hantosi, Dóra and Hunya, Ákos and Bari, Ferenc and Horváth, Ibolya and Vigh, László and Farkas, Eszter}, doi = {10.1111/bph.14611}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, volume = {176}, unique-id = {30431480}, issn = {0007-1188}, abstract = {A new class of heat shock protein co-inducer dihydropyridine derivatives devoid of calcium channel antagonist and vasodilator effects have been recently developed with the purpose to target neurodegeneration selectively. Here we set out to evaluate the action of one of these novel compounds LA1011 on neurovascular coupling in the ischemic rat cerebral cortex. As a reference, we applied nimodipine, a well-known calcium channel antagonist, vasodilator dihydropyridine compound.Rats (n=62) were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011, 1 mg/kg b.w.), or acute, local administration (LA1011 and nimodipine, 100 μM). In the latter treatment group, global forebrain ischemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anesthesia. Functional hyperemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under alpha-chloralose anesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry.LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect. Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperemia in response to both somatosensory stimulation and SD, particularly under ischemia. In conclusion, in contrast with CBF improvement achieved by nimodipine, LA1011 seems not to have discernible cerebrovascular effects, but may upregulate stress response.}, year = {2019}, eissn = {1476-5381}, pages = {1222-1234}, orcid-numbers = {Varga, Dániel Péter/0000-0001-5797-9334; Menyhárt, Ákos/0000-0002-1355-3208; Hunya, Ákos/0000-0002-4547-9284; Farkas, Eszter/0000-0002-8478-9664} } @article{MTMT:31665750, title = {Miért csillapított a stresszválasz az öregedés során, avagy a dajkafehérje expresszió és a membrán-fluiditás kapcsolata}, url = {https://m2.mtmt.hu/api/publication/31665750}, author = {Benkő, Sándor and Balogh, Gábor and Péter, Mária and Török, Zsolt and Gombos, Imre and Glatz, Attila and Horváth, Ibolya and Vigh, László}, journal-iso = {IDŐSGYÓGYÁSZAT}, journal = {IDŐSGYÓGYÁSZAT}, volume = {3}, unique-id = {31665750}, issn = {2498-8057}, year = {2018}, pages = {42-47}, orcid-numbers = {Benkő, Sándor/0000-0002-9379-8503} } @article{MTMT:30385388, title = {Poly(ADP-ribose) polymerase-2 is a lipid-modulated modulator of muscular lipid homeostasis}, url = {https://m2.mtmt.hu/api/publication/30385388}, author = {Márton, Judit and Péter, Mária and Balogh, Gábor and Bódi, Beáta and Vida, András and Szántó, Magdolna and Bojcsuk, Dóra and Jankó, Laura and Bhattoa Harjit, Pál and Gombos, Imre and Uray (Davis), Karen L. and Horváth, Ibolya and Török, Zsolt and Bálint, Bálint László and Papp, Zoltán and Vigh, László and Bay, Péter}, doi = {10.1016/j.bbalip.2018.07.013}, journal-iso = {BBA-MOL CELL BIOL L}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS}, volume = {1863}, unique-id = {30385388}, issn = {1388-1981}, abstract = {There is a growing body of evidence that poly(ADP-ribose) polymerase-2 (PARP2), although originally described as a DNA repair protein, has a widespread role as a metabolic regulator. We show that the ablation of PARP2 induced characteristic changes in the lipidome. The silencing of PARP2 induced the expression of sterol regulatory element-binding protein-1 and -2 and initiated de novo cholesterol biosynthesis in skeletal muscle. Increased muscular cholesterol was shunted to muscular biosynthesis of dihydrotestosterone, an anabolic steroid. Thus, skeletal muscle fibers in PARP2(-/-) mice were stronger compared to those of their wild-type littermates. In addition, we detected changes in the dynamics of the cell membrane, suggesting that lipidome changes also affect the biophysical characteristics of the cell membrane. In in silico and wet chemistry studies, we identified lipid species that can decrease the expression of PARP2 and potentially phenocopy the genetic abruption of PARP2, including artificial steroids. In view of these observations, we propose a new role for PARP2 as a lipid-modulated regulator of lipid metabolism.}, year = {2018}, eissn = {1879-2618}, pages = {1399-1412}, orcid-numbers = {Bojcsuk, Dóra/0000-0001-5091-7237; Bhattoa Harjit, Pál/0000-0002-4909-0065; Bálint, Bálint László/0000-0002-6163-7190} } @article{MTMT:27698958, title = {Dihydropyridines allosterically modulate Hsp90 providing a novel mechanism for heat shock protein co-induction and neuroprotection}, url = {https://m2.mtmt.hu/api/publication/27698958}, author = {Roe, MS and Wahab, B and Török, Zsolt and Horváth, Ibolya and Vigh, László and Prodromou, C}, doi = {10.3389/fmolb.2018.00051}, journal-iso = {FRONT MOL BIOSCI}, journal = {FRONTIERS IN MOLECULAR BIOSCIENCES}, volume = {5}, unique-id = {27698958}, abstract = {Chaperones play a pivotal role in protein homeostasis, but with age their ability to clear aggregated and damaged protein from cells declines. Tau pathology is a driver of a variety of neurodegenerative disease and in Alzheimer's disease (AD) it appears to be precipitated by the formation of amyloid-beta (beta) aggregates. A beta-peptide appears to trigger Tau hyperphosphorylation, formation of neurofibrillary tangles and neurotoxicity. Recently, dihydropyridine derivatives were shown to upregulate the heat shock response (HSR) and provide a neuroprotective effect in an APPxPS1 AD mouse model. The HSR response was only seen in diseased cells and consequently these compounds were defined as co-inducers since they upregulate chaperones and co-chaperones only when a pathological state is present. We show for compounds tested herein, that they target predominantly the C-terminal domain of Hsp90, but show some requirement for its middle-domain, and that binding stimulates the chaperones ATPase activity. We identify the site for LA1011 binding and confirm its identification by mutagenesis. We conclude, that binding compromises Hsp90's ability to chaperone, by modulating its ATPase activity, which consequently induces the HSR in diseased cells. Collectively, this represents the mechanism by which the normalization of neurofibrillary tangles, preservation of neurons, reduced tau pathology, reduced amyloid plaque, and increased dendritic spine density in the APPxPS1 Alzheimer's mouse model is initiated. Such dihydropyridine derivatives therefore represent potential pharmaceutical candidates for the therapy of neurodegenerative disease, such as AD.}, year = {2018}, eissn = {2296-889X} } @article{MTMT:3411899, title = {Chemotherapy induced PRL3 expression promotes cancer growth via plasma membrane remodeling and specific alterations of caveolae-associated signaling}, url = {https://m2.mtmt.hu/api/publication/3411899}, author = {Csoboz, Bálint and Gombos, Imre and Tátrai, Enikő and Tóvári, József and L. Kiss, Anna and Horváth, Ibolya and Vigh, László}, doi = {10.1186/s12964-018-0264-8}, journal-iso = {CELL COMM SIGN}, journal = {CELL COMMUNICATION AND SIGNALING}, volume = {16}, unique-id = {3411899}, issn = {1478-811X}, abstract = {BACKGROUND: The outcome of cancer therapy is greatly defined by the ability of a tumor cell to evade treatment and re-establish its bulk mass after medical interventions. Consequently, there is an urgent need for the characterization of molecules affecting tumor reoccurrence. The phosphatase of regenerating liver 3 (PRL3) protein was recently emerged among the targets that could affect such a phenomenon. METHODS: The expression induction of PRL3 in melanoma cells treated with chemotherapeutic agents was assessed by western blotting. The effect of PRL3 expression on cancer growth was investigated both in vitro and in vivo. The association of PRL3 with the caveolae structures of the plasma membrane was analyzed by detergent free raft purification. The effect of PRL3 expression on the membrane organization was assayed by electron microscopy and by membrane biophysical measurements. Purification of the plasma membrane fraction and co-immunoprecipitation were used to evaluate the altered protein composition of the plasma membrane upon PRL3 expression. RESULTS: Here, we identified PRL3 as a genotoxic stress-induced oncogene whose expression is significantly increased by the presence of classical antitumor therapeutics. Furthermore, we successfully connected the presence of this oncogene with increased tumor growth, which implies that tumor cells can utilize PRL3 effects as a survival strategy. We further demonstrated the molecular mechanism that is connected with the pro-growth action of PRL3, which is closely associated with its localization to the caveolae-type lipid raft compartment of the plasma membrane. In our study, PRL3 was associated with distinct changes in the plasma membrane structure and in the caveolar proteome, such as the dephosphorylation of integrin beta1 at Thr788/Thr789 and the increased partitioning of Rac1 to the plasma membrane. These alterations at the plasma membrane were further associated with the elevation of cyclin D1 in the nucleus. CONCLUSIONS: This study identifies PRL3 as an oncogene upregulated in cancer cells upon exposure to anticancer therapeutics. Furthermore, this work contributes to the existing knowledge on PRL3 function by characterizing its association with the caveolae-like domains of the plasma membrane and their resident proteins.}, year = {2018}, eissn = {1478-811X}, orcid-numbers = {Tátrai, Enikő/0000-0001-9778-2077; Tóvári, József/0000-0002-5543-3204} } @article{MTMT:3305696, title = {Mild heat induces a distinct "eustress" response in Chinese Hamster Ovary cells but does not induce heat shock protein synthesis}, url = {https://m2.mtmt.hu/api/publication/3305696}, author = {Peksel, Begüm and Gombos, Imre and Péter, Mária and Vígh, László Jr. and Tiszlavicz, Ádám and Brameshuber, M and Balogh, Gábor and Schutz, GJ and Horváth, Ibolya and Vigh, László and Török, Zsolt}, doi = {10.1038/s41598-017-15821-8}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {7}, unique-id = {3305696}, issn = {2045-2322}, abstract = {The current research on cellular heat stress management focuses on the roles of heat shock proteins (HSPs) and the proteostasis network under severe stress conditions. The mild, fever-type stress and the maintenance of membrane homeostasis are less well understood. Herein, we characterized the acute effect of mild, fever-range heat shock on membrane organization, and HSP synthesis and localization in two mammalian cell lines, to delineate the role of membranes in the sensing and adaptation to heat. A multidisciplinary approach combining ultrasensitive fluorescence microscopy and lipidomics revealed the molecular details of novel cellular "eustress", when cells adapt to mild heat by maintaining membrane homeostasis, activating lipid remodeling, and redistributing chaperone proteins. Notably, this leads to acquired thermotolerance in the complete absence of the induction of HSPs. At higher temperatures, additional defense mechanisms are activated, including elevated expression of molecular chaperones, contributing to an extended stress memory and acquired thermotolerance.}, keywords = {LOCALIZATION; PLASMA-MEMBRANE; ACTIVATION; ESCHERICHIA-COLI; GPI-ANCHORED PROTEINS; INDUCED APOPTOSIS; Hsp70; THERMOTOLERANCE; PHOSPHATIDIC-ACID; STRESS-PROTEINS}, year = {2017}, eissn = {2045-2322} } @article{MTMT:3200680, title = {Metabolic crosstalk between membrane and storage lipids facilitates heat stress management in Schizosaccharomyces pombe.}, url = {https://m2.mtmt.hu/api/publication/3200680}, author = {Péter, Mária and Glatz, Attila and Gudmann, Péter and Gombos, Imre and Török, Zsolt and Horváth, Ibolya and Vigh, László and Balogh, Gábor}, doi = {10.1371/journal.pone.0173739}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {12}, unique-id = {3200680}, issn = {1932-6203}, abstract = {Cell membranes actively participate in stress sensing and signalling. Here we present the first in-depth lipidomic analysis to characterize alterations in the fission yeast Schizosaccharomyces pombe in response to mild heat stress (HS). The lipidome was assessed by a simple one-step methanolic extraction. Genetic manipulations that altered triglyceride (TG) content in the absence or presence of HS gave rise to distinct lipidomic fingerprints for S. pombe. Cells unable to produce TG demonstrated long-lasting growth arrest and enhanced signalling lipid generation. Our results reveal that metabolic crosstalk between membrane and storage lipids facilitates homeostatic maintenance of the membrane physical/chemical state that resists negative effects on cell growth and viability in response to HS. We propose a novel stress adaptation mechanism in which heat-induced TG synthesis contributes to membrane rigidization by accommodating unsaturated fatty acids of structural lipids, enabling their replacement by newly synthesized saturated fatty acids.}, year = {2017}, eissn = {1932-6203} }