TY  - JOUR
A1  - Hupp, Sabrina
A1  - Förtsch, Christina
A1  - Wippel, Carolin
A1  - Ma, Jiangtao
A1  - Mitchell, Timothy J.
A1  - Iliev, Asparouh I.
T1  - Direct Transmembrane Interaction between Actin and the Pore-Competent, Cholesterol-Dependent Cytolysin Pneumolysin
JF  - Journal of Molecular Biology
N2  - The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by Förster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170–190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought.
KW  - pore-forming toxin
KW  - cholesterol-dependent cytolysin
KW  - actin
KW  - membrane
KW  - pneumolysin
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132297
VL  - 425
IS  - 3
ER  - 
TY  - JOUR
A1  - Bogdan, Sven
A1  - Schultz, Jörg
A1  - Grosshans, Jörg
T1  - Formin’ cellular structures: Physiological roles of Diaphanous (Dia) in actin dynamics
JF  - Communicative & Integrative Biology
N2  - Members of the Diaphanous (Dia) protein family are key regulators of fundamental actin driven cellular processes, which are conserved from yeast to humans. Researchers have uncovered diverse physiological roles in cell morphology, cell motility, cell polarity, and cell division, which are involved in shaping cells into tissues and organs. The identification of numerous binding partners led to substantial progress in our understanding of the differential functions of Dia proteins. Genetic approaches and new microscopy techniques allow important new insights into their localization, activity, and molecular principles of regulation.
KW  - Drosophila
KW  - cytoskeleton
KW  - actin
KW  - nucleator
KW  - development
KW  - formin
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121305
VL  - 6
IS  - e27634
ER  - 
TY  - JOUR
A1  - Benz, Peter M.
A1  - Merkel, Carla J.
A1  - Offner, Kristin
A1  - Abeßer, Marco
A1  - Ullrich, Melanie
A1  - Fischer, Tobias
A1  - Bayer, Barbara
A1  - Wagner, Helga
A1  - Gambaryan, Stepan
A1  - Ursitti, Jeanine A.
A1  - Adham, Ibrahim M.
A1  - Linke, Wolfgang A.
A1  - Feller, Stephan M.
A1  - Fleming, Ingrid
A1  - Renné, Thomas
A1  - Frantz, Stefan
A1  - Unger, Andreas
A1  - Schuh, Kai
T1  - Mena/VASP and alphaII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy
JF  - Cell Communication and Signaling
N2  - Background: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
Results: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
Conclusions: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
KW  - Mena/VASP
KW  - dilated cardiomyopathy
KW  - actin
KW  - heart
KW  - spectrin
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128760
VL  - 11
IS  - 56
ER  -