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Article ; Online: The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection

Marco Kirchenwitz / Stephanie Stahnke / Kyra Grunau / Lars Melcher / Marco van Ham / Klemens Rottner / Anika Steffen / Theresia E. B. Stradal

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 14

Abstract: Abstract SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was ... ...

Abstract	Abstract SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy acting independently of the mTOR pathway, increasing autophagosome biosynthesis and attenuating mutant huntingtin-fragment toxicity in cellular- and fruit fly disease models, suggesting therapeutic potential. Despite many previous studies, molecular mechanisms mediating SMER28 activities and its direct targets have remained elusive. Here we analyzed the effects of SMER28 on cells and found that aside from autophagy induction, it significantly stabilizes microtubules and decelerates microtubule dynamics. Moreover, we report that SMER28 displays neurotrophic and neuroprotective effects at the cellular level by inducing neurite outgrowth and protecting from excitotoxin-induced axon degeneration. Finally, we compare the effects of SMER28 with other autophagy-inducing or microtubule-stabilizing drugs: whereas SMER28 and rapamycin both induce autophagy, the latter does not stabilize microtubules, and whereas both SMER28 and epothilone B stabilize microtubules, epothilone B does not stimulate autophagy. Thus, the effect of SMER28 on cells in general and neurons in particular is based on its unique spectrum of bioactivities distinct from other known microtubule-stabilizing or autophagy-inducing drugs.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta

Marco Kirchenwitz / Stephanie Stahnke / Silvia Prettin / Malgorzata Borowiak / Laura Menke / Christian Sieben / Carmen Birchmeier / Klemens Rottner / Theresia E. B. Stradal / Anika Steffen

Cells, Vol 11, Iss 1648, p

2022 Volume 1648

Abstract: SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also ... ...

Abstract	SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes , which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity.
Keywords	phosphatidylinositol 3-kinase (PI 3-kinase) ; mammalian target of rapamycin (mTOR) ; autophagy ; receptor tyrosine kinase ; small molecule ; actin ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neurotrophic and Immunomodulatory Lanostane Triterpenoids from Wood-Inhabiting Basidiomycota

Khadija Hassan / Blondelle Matio Kemkuignou / Marco Kirchenwitz / Kathrin Wittstein / Monique Rascher-Albaghdadi / Clara Chepkirui / Josphat C. Matasyoh / Cony Decock / Reinhard W. Köster / Theresia E. B. Stradal / Marc Stadler

International Journal of Molecular Sciences, Vol 23, Iss 13593, p

2022 Volume 13593

Abstract: Neurotrophins such as nerve growth factor (ngf) and brain-derived neurotrophic factor (bdnf) play important roles in the central nervous system. They are potential therapeutic drugs for the treatment of neurodegenerative diseases, including Alzheimer’s ... ...

Abstract	Neurotrophins such as nerve growth factor (ngf) and brain-derived neurotrophic factor (bdnf) play important roles in the central nervous system. They are potential therapeutic drugs for the treatment of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. In this study, we investigated the neurotrophic properties of triterpenes isolated from fruiting bodies of Laetiporus sulphureus and a mycelial culture of Antrodia sp. MUCL 56049. The structures of the isolated compounds were elucidated based on nuclear magnetic resonance (NMR) spectroscopy in combination with high-resolution electrospray mass spectrometry (HR-ESIMS). The secondary metabolites were tested for neurotrophin (ngf and bdnf ) expression levels on human astrocytoma 1321N1 cells. Neurite outgrowth activity using rat pheochromocytoma (PC-12) cells was also determined. Twelve triterpenoids were isolated, of which several potently stimulated the expression of neurotrophic factors, namely, ngf (sulphurenic acid, 15α-dehydroxytrametenolic acid, fomefficinic acid D, and 16α-hydroxyeburicoic acid) and bdnf (sulphurenic acid and 15α-dehydroxytrametenolic acid), respectively. The triterpenes also potentiated ngf-induced neurite outgrowth in PC-12 cells. This is, to the best of our knowledge, the first report on the compound class of lanostanes in direct relation to bdnf and ngf enhancement. These compounds are widespread in medicinal mushrooms; hence, they appear promising as a starting point for the development of drugs and mycopharmaceuticals to combat neurodegenerative diseases. Interestingly, they do not show any pronounced cytotoxicity and may, therefore, be better suited for therapy than many other neurotrophic compounds that were previously reported.
Keywords	neurodegenerative diseases ; ngf ; bdnf ; triterpenoids ; pheochromocytoma cells ; astrocytoma cells ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antiproliferative and Cytotoxic Cytochalasins from Sparticola triseptata Inhibit Actin Polymerization and Aggregation

Katherine Yasmin M. Garcia / Mark Tristan J. Quimque / Christopher Lambert / Katharina Schmidt / Gian Primahana / Theresia E. B. Stradal / Andreas Ratzenböck / Hans-Martin Dahse / Chayanard Phukhamsakda / Marc Stadler / Frank Surup / Allan Patrick G. Macabeo

Journal of Fungi, Vol 8, Iss 560, p

2022 Volume 560

Abstract: Laying the groundwork on preliminary structure–activity relationship study relating to the disruptive activity of cytochalasan derivatives on mammalian cell actin cytoskeleton, we furthered our study on the cytochalasans of the Dothideomycetes fungus, ... ...

Abstract	Laying the groundwork on preliminary structure–activity relationship study relating to the disruptive activity of cytochalasan derivatives on mammalian cell actin cytoskeleton, we furthered our study on the cytochalasans of the Dothideomycetes fungus, Sparticola triseptata . A new cytochalasan analog triseptatin ( 1 ), along with the previously described cytochalasans deoxaphomin B ( 2 ) and cytochalasin B ( 3 ), and polyketide derivatives cis -4-hydroxy-6-deoxyscytalone ( 4 ) and 6-hydroxymellein ( 5 ) were isolated from the rice culture of S. triseptata . The structure of 1 was elucidated through NMR spectroscopic analysis and high-resolution mass spectrometry (HR-ESI-MS). The relative and absolute configurations were established through analysis of NOESY spectroscopic data and later correlated with experimental electronic circular dichroism and time-dependent density functional theory (ECD–TDDFT) computational analysis. Compounds 1 and 2 showed cytotoxic activities against seven mammalian cell lines (L929, KB3.1, MCF-7, A549, PC-3, SKOV-3, and A431) and antiproliferative effects against the myeloid leukemia K-562 cancer cell line. Both 1 and 2 were shown to possess properties inhibiting the F-actin network, prompting further hypotheses that should to be tested in the future to enable a well-resolved concept of the structural implications determining the bioactivity of the cytochalasin backbone against F-actin.
Keywords	Sparticola triseptata ; structure elucidation ; ECD–TDDFT ; antiproliferative ; cytotoxic ; actin inhibitors ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Induced Arp2/3 Complex Depletion Increases FMNL2/3 Formin Expression and Filopodia Formation

Vanessa Dimchev / Ines Lahmann / Stefan A. Koestler / Frieda Kage / Georgi Dimchev / Anika Steffen / Theresia E. B. Stradal / Franz Vauti / Hans-Henning Arnold / Klemens Rottner

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract: The Arp2/3 complex generates branched actin filament networks operating in cell edge protrusion and vesicle trafficking. Here we employ a conditional knockout mouse model permitting tissue- or cell-type specific deletion of the murine Actr3 gene ( ... ...

Abstract	The Arp2/3 complex generates branched actin filament networks operating in cell edge protrusion and vesicle trafficking. Here we employ a conditional knockout mouse model permitting tissue- or cell-type specific deletion of the murine Actr3 gene (encoding Arp3). A functional Actr3 gene appeared essential for fibroblast viability and growth. Thus, we developed cell lines for exploring the consequences of acute, tamoxifen-induced Actr3 deletion causing near-complete loss of functional Arp2/3 complex expression as well as abolished lamellipodia formation and membrane ruffling, as expected. Interestingly, Arp3-depleted cells displayed enhanced rather than reduced cell spreading, employing numerous filopodia, and showed little defects in the rates of random cell migration. However, both exploration of new space by individual cells and collective migration were clearly compromised by the incapability to efficiently maintain directionality of migration, while the principal ability to chemotax was only moderately affected. Examination of actin remodeling at the cell periphery revealed reduced actin turnover rates in Arp2/3-deficient cells, clearly deviating from previous sequestration approaches. Most surprisingly, induced removal of Arp2/3 complexes reproducibly increased FMNL formin expression, which correlated with the explosive induction of filopodia formation. Our results thus highlight both direct and indirect effects of acute Arp2/3 complex removal on actin cytoskeleton regulation.
Keywords	F-actin branching ; lamellipodium ; filopodium ; migration ; chemotaxis ; F-actin turnover ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Resolution of the Hypoxylon fuscum Complex (Hypoxylaceae, Xylariales) and Discovery and Biological Characterization of Two of Its Prominent Secondary Metabolites

Christopher Lambert / Mohammad Javad Pourmoghaddam / Marjorie Cedeño-Sanchez / Frank Surup / Seyed Akbar Khodaparast / Irmgard Krisai-Greilhuber / Hermann Voglmayr / Theresia E. B. Stradal / Marc Stadler

Journal of Fungi, Vol 7, Iss 2, p

2021 Volume 131

Abstract: Hypoxylon, a large, cosmopolitan genus of Ascomycota is in the focus of our current poly-thetic taxonomic studies, and served as an excellent source for bioactive secondary metabolites at the same time. The present work concerns a survey of the Hypoxylon ...

Abstract	Hypoxylon, a large, cosmopolitan genus of Ascomycota is in the focus of our current poly-thetic taxonomic studies, and served as an excellent source for bioactive secondary metabolites at the same time. The present work concerns a survey of the Hypoxylon fuscum species complex based on specimens from Iran and Europe by morphological studies and high performance liquid chromatography coupled to mass spectrometry and diode array detection (HPLC-MS-DAD). Apart from known chemotaxonomic markers like binaphthalene tetrol (BNT) and daldinin F, two unprece-dented molecules were detected and subsequently isolated to purity by semi preparative HPLC. Their structures were established by nuclear-magnetic resonance (NMR) spectroscopy as 3′-malonyl-daldinin F ( 6 ) and pseudofuscochalasin A ( 4 ). The new daldinin derivative 6 showed weak cytotoxicity towards mammalian cells but bactericidal activity. The new cytochalasin 4 was compared to cytochalasin C in an actin disruption assay using fluorescence microscopy of human osteo-sarcoma U2OS cells, revealing comparable activity towards F-actin but being irreversible compared to cytochalasin C. Concurrently, a multilocus molecular phylogeny based on ribosomal and proteinogenic nucleotide sequences of Hypoxylon species resulted in a well-supported clade for H. fuscum and its allies. From a comparison of morphological, chemotaxonomic and phylogenetic evidence, we introduce the new species H. eurasiaticum and H. pseudofuscum .
Keywords	analytical chemistry ; Ascomycota ; bioactivity screening chemotaxonomy ; molecular phylogenetics ; polyphasic taxonomy ; two new species ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Visualization of translocons in Yersinia type III protein secretion machines during host cell infection.

Theresa Nauth / Franziska Huschka / Michaela Schweizer / Jens B Bosse / Andreas Diepold / Antonio Virgilio Failla / Anika Steffen / Theresia E B Stradal / Manuel Wolters / Martin Aepfelbacher

PLoS Pathogens, Vol 14, Iss 12, p e

2018 Volume 1007527

Abstract: Type III secretion systems (T3SSs) are essential virulence factors of numerous bacterial pathogens. Upon host cell contact the T3SS machinery-also named injectisome-assembles a pore complex/translocon within host cell membranes that serves as an entry ... ...

Abstract	Type III secretion systems (T3SSs) are essential virulence factors of numerous bacterial pathogens. Upon host cell contact the T3SS machinery-also named injectisome-assembles a pore complex/translocon within host cell membranes that serves as an entry gate for the bacterial effectors. Whether and how translocons are physically connected to injectisome needles, whether their phenotype is related to the level of effector translocation and which target cell factors trigger their formation have remained unclear. We employed the superresolution fluorescence microscopy techniques Stimulated Emission Depletion (STED) and Structured Illumination Microscopy (SIM) as well as immunogold electron microscopy to visualize Y. enterocolitica translocons during infection of different target cell types. Thereby we were able to resolve translocon and needle complex proteins within the same injectisomes and demonstrate that these fully assembled injectisomes are generated in a prevacuole, a PI(4,5)P2 enriched host cell compartment inaccessible to large extracellular proteins like antibodies. Furthermore, the operable translocons were produced by the yersiniae to a much larger degree in macrophages (up to 25% of bacteria) than in HeLa cells (2% of bacteria). However, when the Rho GTPase Rac1 was activated in the HeLa cells, uptake of the yersiniae into the prevacuole, translocon formation and effector translocation were strongly enhanced reaching the same levels as in macrophages. Our findings indicate that operable T3SS translocons can be visualized as part of fully assembled injectisomes with superresolution fluorescence microscopy techniques. By using this technology, we provide novel information about the spatiotemporal organization of T3SS translocons and their regulation by host cell factors.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methylation of Salmonella Typhimurium flagella promotes bacterial adhesion and host cell invasion

Julia A. Horstmann / Michele Lunelli / Hélène Cazzola / Johannes Heidemann / Caroline Kühne / Pascal Steffen / Sandra Szefs / Claire Rossi / Ravi K. Lokareddy / Chu Wang / Laurine Lemaire / Kelly T. Hughes / Charlotte Uetrecht / Hartmut Schlüter / Guntram A. Grassl / Theresia E. B. Stradal / Yannick Rossez / Michael Kolbe / Marc Erhardt

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 11

Abstract: Flagellin proteins of Salmonella flagella are methylated. Here, the authors show that flagellin methylation facilitates adhesion of Salmonella to hydrophobic host-cell surfaces, and contributes to efficient gut colonization and host infection. ...

Abstract	Flagellin proteins of Salmonella flagella are methylated. Here, the authors show that flagellin methylation facilitates adhesion of Salmonella to hydrophobic host-cell surfaces, and contributes to efficient gut colonization and host infection.
Keywords	Science ; Q
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methylation of Salmonella Typhimurium flagella promotes bacterial adhesion and host cell invasion

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 11

Abstract	Flagellin proteins of Salmonella flagella are methylated. Here, the authors show that flagellin methylation facilitates adhesion of Salmonella to hydrophobic host-cell surfaces, and contributes to efficient gut colonization and host infection.
Keywords	Science ; Q
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: FMNL formins boost lamellipodial force generation

Frieda Kage / Moritz Winterhoff / Vanessa Dimchev / Jan Mueller / Tobias Thalheim / Anika Freise / Stefan Brühmann / Jana Kollasser / Jennifer Block / Georgi Dimchev / Matthias Geyer / Hans-Joachim Schnittler / Cord Brakebusch / Theresia E. B. Stradal / Marie-France Carlier / Michael Sixt / Josef Käs / Jan Faix / Klemens Rottner

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

2017 Volume 16

Abstract: Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion ... ...

Abstract	Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.
Keywords	Science ; Q
Language	English
Publishing date	2017-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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