TY  - JOUR
A1  - Schwan, Carsten
A1  - Lang, Alexander E.
A1  - Schlosser, Andreas
A1  - Fujita-Becker, Setsuko
A1  - AlHaj, Abdulatif
A1  - Schröder, Rasmus R.
A1  - Faix, Jan
A1  - Aktories, Klaus
A1  - Mannherz, Hans Georg
T1  - Inhibition of Arp2/3 complex after ADP-ribosylation of Arp2 by binary Clostridioides toxins
JF  - Cells
N2  - Clostridioides bacteria are responsible for life threatening infections. Here, we show that in addition to actin, the binary toxins CDT, C2I, and Iota from Clostridioides difficile, botulinum, and perfrigens, respectively, ADP-ribosylate the actin-related protein Arp2 of Arp2/3 complex and its additional components ArpC1, ArpC2, and ArpC4/5. The Arp2/3 complex is composed of seven subunits and stimulates the formation of branched actin filament networks. This activity is inhibited after ADP-ribosylation of Arp2. Translocation of the ADP-ribosyltransferase component of CDT toxin into human colon carcinoma Caco2 cells led to ADP-ribosylation of cellular Arp2 and actin followed by a collapse of the lamellipodial extensions and F-actin network. Exposure of isolated mouse colon pieces to CDT toxin induced the dissolution of the enterocytes leading to luminal aggregation of cellular debris and the collapse of the mucosal organization. Thus, we identify the Arp2/3 complex as hitherto unknown target of clostridial ADP-ribosyltransferases.
KW  - actin
KW  - ADP-ribosyltransferases
KW  - Arp2/3 complex
KW  - Clostridioides binary toxins
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297454
SN  - 2073-4409
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Budde, Heidi
A1  - Hassoun, Roua
A1  - Tangos, Melina
A1  - Zhazykbayeva, Saltanat
A1  - Herwig, Melissa
A1  - Varatnitskaya, Marharyta
A1  - Sieme, Marcel
A1  - Delalat, Simin
A1  - Sultana, Innas
A1  - Kolijn, Detmar
A1  - Gömöri, Kamilla
A1  - Jarkas, Muhammad
A1  - Lódi, Mária
A1  - Jaquet, Kornelia
A1  - Kovács, Árpád
A1  - Mannherz, Hans Georg
A1  - Sequeira, Vasco
A1  - Mügge, Andreas
A1  - Leichert, Lars I.
A1  - Sossalla, Samuel
A1  - Hamdani, Nazha
T1  - The interplay between S-glutathionylation and phosphorylation of cardiac troponin I and myosin binding protein C in end-stage human failing hearts
JF  - Antioxidants
N2  - Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca\(^{2+}\)-activated tension and Ca\(^{2+}\) sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca\(^{2+}\) sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.
KW  - myofilament proteins
KW  - oxidative stress
KW  - inflammation
KW  - phosphorylation
KW  - S-glutathionylation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242701
SN  - 2076-3921
VL  - 10
IS  - 7
ER  -