TY - JOUR AU - Letoha, Annamária AU - Hudák, Anett AU - Bozsó, Zsolt AU - Vizler, Csaba AU - Veres, Gábor AU - Szilák, László AU - Letoha, Tamás TI - The Nuclear Localization Signal of NF-κB p50 Enters the Cells via Syndecan-Mediated Endocytosis and Inhibits NF-κB Activity JF - INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS J2 - INT J PEPT RES THER VL - 29 PY - 2023 IS - 5 PG - 16 SN - 1573-3149 DO - 10.1007/s10989-023-10548-9 UR - https://m2.mtmt.hu/api/publication/34050718 ID - 34050718 AB - It is well established that cationic peptides can enter cells following attachment to polyanionic membrane components. We report that the basic nuclear localization signal (NLS) of the NF-κB p50 subunit is internalized via lipid raft-dependent endocytosis mediated by heparan sulfate proteoglycans and exerts significant NF-κB inhibitory activities both in vitro and in vivo. In vitro uptake experiments revealed that the p50 NLS peptide (CYVQRKRQKLMP) enters the cytoplasm and accumulates in the nucleus at 37 °C. Depleting cellular ATP pools or decreasing temperature to 4 °C abolished peptide internalization, confirming the active, energy-dependent endocytic uptake. Co-incubation with heparan sulfate or replacing the peptide’s basic residues with glycines markedly reduced the intracellular entry of the p50 NLS, referring to the role of polyanionic cell-surface proteoglycans in internalization. Furthermore, treatment with methyl-β-cyclodextrin greatly inhibited the peptide’s membrane translocation. Overexpression of the isoforms of the syndecan family of transmembrane proteoglycans, especially syndecan-4, increased the cellular internalization of the NLS, suggesting syndecans’ involvement in the peptide’s cellular uptake. In vitro , p50 NLS reduced NF-κB activity in TNF-α-induced L929 fibroblasts and LPS-stimulated RAW 264.7 macrophages. TNF-α-induced ICAM-1 expression of HMEC-1 human endothelial cells could also be inhibited by the peptide. Fifteen minutes after its intraperitoneal injection, the peptide rapidly entered the cells of the pancreas, an organ with marked syndecan-4 expression. In an acute pancreatitis model, an inflammatory disorder triggered by the activation of stress-responsive transcription factors like NF-κB, administration of the p50 NLS peptide reduced the severity of pancreatic inflammation by blocking NF-κB transcription activity and ameliorating the examined laboratory and histological markers of pancreatitis. LA - English DB - MTMT ER - TY - JOUR AU - Ughy, Bettina AU - Nagyapáti, Sarolta AU - Lajkó, Dézi Bianka AU - Letoha, Tamas AU - Prohaszka, Adam AU - Deeb, Dima AU - Dér, András AU - Pettkó-Szandtner, Aladár AU - Szilák, László TI - Reconsidering Dogmas about the Growth of Bacterial Populations JF - CELLS J2 - CELLS-BASEL VL - 12 PY - 2023 IS - 10 PG - 15 SN - 2073-4409 DO - 10.3390/cells12101430 UR - https://m2.mtmt.hu/api/publication/33846356 ID - 33846356 N1 - Funding Agency and Grant Number: Hungarian Ministry for National Economy and National Research Development and Innovation Office of Hungary [GINOP-2.3.2-15-2016-00058]; European Union [101000501] Funding text: This research was funded by grants of the Hungarian Ministry for National Economy and National Research Development and Innovation Office of Hungary (GINOP-2.3.2-15-2016-00058) and the European Unions Horizon 2020 Research and Innovation Program under grant agreement No 101000501. AB - The growth of bacterial populations has been described as a dynamic process of continuous reproduction and cell death. However, this is far from the reality. In a well fed, growing bacterial population, the stationary phase inevitably occurs, and it is not due to accumulated toxins or cell death. A population spends the most time in the stationary phase, where the phenotype of the cells alters from the proliferating ones, and only the colony forming unit (CFU) decreases after a while, not the total cell concentration. A bacterial population can be considered as a virtual tissue as a result of a specific differentiation process, in which the exponential-phase cells develop to stationary-phase cells and eventually reach the unculturable form. The richness of the nutrient had no effect on growth rate or on stationary cell density. The generation time seems not to be a constant value, but it depended on the concentration of the starter cultures. Inoculations with serial dilutions of stationary populations reveal a so-called minimal stationary cell concentration (MSCC) point, up to which the cell concentrations remain constant upon dilutions; that seems to be universal among unicellular organisms. LA - English DB - MTMT ER - TY - JOUR AU - Hudák, Anett AU - Roach, Matthew AU - Pusztai, Dávid AU - Pettkó-Szandtner, Aladár AU - Letoha, Annamária AU - Szilák, László AU - Azzouz, Mimoun AU - Letoha, Tamás TI - Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 4 PG - 17 SN - 1661-6596 DO - 10.3390/ijms24043141 UR - https://m2.mtmt.hu/api/publication/33630992 ID - 33630992 N1 - Export Date: 26 April 2023 AB - Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS. LA - English DB - MTMT ER - TY - JOUR AU - Hudak, Anett AU - Morgan, Gareth AU - Bacovsky, Jaromir AU - Patai, Roland AU - Polgár, Tamás Ferenc AU - Letoha, Annamaria AU - Pettkó-Szandtner, Aladár AU - Vizler, Csaba AU - Szilák, László AU - Letoha, Tamás TI - Biodistribution and Cellular Internalization of Inactivated SARS-CoV-2 in Wild-Type Mice JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 14 PG - 17 SN - 1661-6596 DO - 10.3390/ijms23147609 UR - https://m2.mtmt.hu/api/publication/33050457 ID - 33050457 N1 - Funding Agency and Grant Number: Innovative Medicines Initiative 2 Joint Undertaking [807015]; European Union; EFPIA; European Union [863214]; National Research, Development, and Innovation Office, Hungary [2020-1.1.6-JOVO-2021-00012]; [2017-2.3.6-TET-CN-2018-00023] Funding text: A.H., L.S. and T.L. received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 807015. This joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. A.H., L.S. and T.L. also received funding from the European Union's Horizon 2020 research and innovation program under Future and Emerging Technologies grant agreement no. 863214. A.H., L.S. and T.L. were also supported by grant no. 2017-2.3.6-TET-CN-2018-00023. A.H., L.S., A.L., P.S.A., C.V. and T.L. were supported by grant no. 2020-1.1.6-JOVO-2021-00012 of the National Research, Development, and Innovation Office, Hungary. AB - Despite the growing list of identified SARS-CoV-2 receptors, the human angiotensin-converting enzyme 2 (ACE2) is still viewed as the main cell entry receptor mediating SARS-CoV-2 internalization. It has been reported that wild-type mice, like other rodent species of the Muridae family, cannot be infected with SARS-CoV-2 due to differences in their ACE2 receptors. On the other hand, the consensus heparin-binding motif of SARS-CoV-2's spike protein, PRRAR, enables the attachment to rodent heparan sulfate proteoglycans (HSPGs), including syndecans, a transmembrane HSPG family with a well-established role in clathrin- and caveolin-independent endocytosis. As mammalian syndecans possess a relatively conserved structure, we analyzed the cellular uptake of inactivated SARS-CoV-2 particles in in vitro and in vivo mice models. Cellular studies revealed efficient uptake into murine cell lines with established syndecan-4 expression. After intravenous administration, inactivated SARS-CoV-2 was taken up by several organs in vivo and could also be detected in the brain. Internalized by various tissues, inactivated SARS-CoV-2 raised tissue TNF-alpha levels, especially in the heart, reflecting the onset of inflammation. Our studies on in vitro and in vivo mice models thus shed light on unknown details of SARS-CoV-2 internalization and help broaden the understanding of the molecular interactions of SARS-CoV-2. LA - English DB - MTMT ER - TY - JOUR AU - Hudák, Anett AU - Veres, Gábor AU - Letoha, Annamária AU - Szilák, László AU - Letoha, Tamás TI - Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 2 PG - 19 SN - 1661-6596 DO - 10.3390/ijms23020796 UR - https://m2.mtmt.hu/api/publication/32599003 ID - 32599003 N1 - Cited By :7 Export Date: 26 April 2023 LA - English DB - MTMT ER - TY - JOUR AU - Kanna, Sai Divya AU - Racskóné Domonkos, Ildikó AU - Kóbori, T.O. AU - Dergez, Ágnes Karolina AU - Böde, Kinga AU - Nagyapáti, Sarolta AU - Zsíros, Ottó AU - Ünnep, Renáta AU - Nagy, Gergely AU - Garab, Győző AU - Szilák, László AU - Solymosi, Katalin AU - Kovács, László AU - Ughy, Bettina TI - Salt Stress Induces Paramylon Accumulation and Fine-Tuning of the Macro-Organization of Thylakoid Membranes in Euglena gracilis Cells JF - FRONTIERS IN PLANT SCIENCE J2 - FRONT PLANT SCI VL - 12 PY - 2021 PG - 15 SN - 1664-462X DO - 10.3389/fpls.2021.725699 UR - https://m2.mtmt.hu/api/publication/32823174 ID - 32823174 LA - English DB - MTMT ER - TY - JOUR AU - Hudak, Anett AU - Jósvay, Katalin AU - Racskóné Domonkos, Ildikó AU - Letoha, Annamária AU - Szilák, László AU - Letoha, Tamás TI - The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 13 PG - 17 SN - 1661-6596 DO - 10.3390/ijms22137070 UR - https://m2.mtmt.hu/api/publication/32106321 ID - 32106321 N1 - Funding Agency and Grant Number: Innovative Medicines Initiative 2 Joint Undertaking [807015]; European Union's Horizon 2020 research and innovation programme; EFPIA; European Union's Horizon 2020 Research and Innovation Programme under Future and Emerging Technologies [863214]; National Research, Development and Innovation Office, HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [GINOP-2.1.2-8-1-4-16-2017-00234, EUREKA_16-1-20170018, 2019-2.1.1-EUREKA-2019-00007, 2017-2.3.6-TET-CN-2018-00023] Funding text: A.H., L.S. and T.L. have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 807015. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. A.H., L.S. and T.L. have also received funding from the European Union's Horizon 2020 Research and Innovation Programme under Future and Emerging Technologies grant agreement No. 863214. A.H., L.S. and T.L. have also been supported by GINOP-2.1.2-8-1-4-16-2017-00234 and grants EUREKA_16-1-20170018, 2019-2.1.1-EUREKA-2019-00007 and 2017-2.3.6-TET-CN-2018-00023 of the National Research, Development and Innovation Office, Hungary. AB - Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer's disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (A beta). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in A beta pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE-heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated A beta uptake and aggregation. ApoE2 increased the cellular internalization of monomeric A beta, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once A beta aggregated: while ApoE2 reduced the uptake of A beta aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4 ' s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of A beta pathology. LA - English DB - MTMT ER - TY - JOUR AU - Reszegi, Andrea AU - Karászi, Katalin AU - Tóth, Gábor AU - Rada, Kristóf Róbert AU - Váncza, Lóránd AU - Turiák, Lilla AU - Schaff, Zsuzsa AU - Kiss, András AU - Szilák, László AU - Szabó, Gábor AU - Petővári, Gábor AU - Sebestyén, Anna AU - Dezső, Katalin AU - Regős, Eszter AU - Tátrai, Péter AU - Baghy, Kornélia AU - Kovalszky, Ilona TI - Overexpression of Human Syndecan-1 Protects against the Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice JF - CANCERS J2 - CANCERS VL - 13 PY - 2021 IS - 7 PG - 33 SN - 2072-6694 DO - 10.3390/cancers13071548 UR - https://m2.mtmt.hu/api/publication/31945022 ID - 31945022 N1 - Funding Agency and Grant Number: Hungarian Scientific Research Fund [67925, 100904, 119283, 128881]; European Union Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange Evaluations (RISE) project [645756]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; National Research, Development and Innovation Fund (New National Excellence Program of the Ministry of Human Capacities) [UNKP-20-4-I-SE-26] Funding text: This research was funded by the Hungarian Scientific Research Fund (grants 67925, 100904 and 119283 to I.K.; grant 128881 to A.K.) and European Union Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange Evaluations (RISE) project (grant 645756): "GLYCANC-Matrix glycans as multifunctional pathogenesis factors and therapeutic targets in cancer" (to I.K.); by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (to L.T.); by the National Research, Development and Innovation Fund (UNKP-20-4-I-SE-26 New National Excellence Program of the Ministry of Human Capacities to A.R.). LA - English DB - MTMT ER - TY - JOUR AU - Hudák, Anett AU - Letoha, Annamária AU - Szilák, László AU - Letoha, Tamás TI - Contribution of syndecans to the cellular entry of SARS-CoV-2 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 10 PG - 27 SN - 1661-6596 DO - 10.3390/ijms22105336 UR - https://m2.mtmt.hu/api/publication/31881380 ID - 31881380 N1 - Pharmacoidea Ltd, Szeged, H-6726, Hungary Department of Medicine, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, Szeged, H-6725, Hungary Szilak Laboratories, Bioinformatics and Molecule-Design, Szeged, H-6723, Hungary Cited By :13 Export Date: 12 September 2022 Correspondence Address: Letoha, T.; Pharmacoidea LtdHungary; email: tamas.letoha@pharmacoidea.eu LA - English DB - MTMT ER - TY - JOUR AU - Hollósi, Péter AU - Váncza, Lóránd AU - Karászi, Katalin AU - Dobos, Katalin AU - Péterfia, Bálint AU - Tátrai, Enikő AU - Tátrai, Péter AU - Szarvas, Tibor AU - Paku, Sándor AU - Szilák, László AU - Kovalszky, Ilona TI - Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1 JF - BIOMOLECULES J2 - BIOMOLECULES VL - 10 PY - 2020 IS - 10 PG - 25 SN - 2218-273X DO - 10.3390/biom10101356 UR - https://m2.mtmt.hu/api/publication/31615706 ID - 31615706 N1 - Funding Agency and Grant Number: Hungarian Scientific Research Fund [67925, 100904, 119283]; European Union Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange Evaluations (RISE) project [645756]; Hungarian National Research, Development and Innovation Office (NKFIH) [NVKP_16-1-2016-0004] Funding text: This research was funded by the Hungarian Scientific Research Fund (grants 67925, 100904, and 119283) and the European Union Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) Research and Innovation Staff Exchange Evaluations (RISE) project (grant 645756), "GLYCANC-Matrix glycans as multifunctional pathogenesis factors and therapeutic targets in cancer". The study and the APC were also funded by the NVKP_16-1-2016-0004 grant of the Hungarian National Research, Development and Innovation Office (NKFIH). LA - English DB - MTMT ER -