@article{FusiPaudelMederetal.2022, author = {Fusi, Lorenza and Paudel, Rupesh and Meder, Katharina and Schlosser, Andreas and Schrama, David and Goebeler, Matthias and Schmidt, Marc}, title = {Interaction of transcription factor FoxO3 with histone acetyltransferase complex subunit TRRAP modulates gene expression and apoptosis}, series = {Journal of Biological Chemistry}, volume = {298}, journal = {Journal of Biological Chemistry}, number = {3}, doi = {10.1016/j.jbc.2022.101714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299820}, year = {2022}, abstract = {Forkhead box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promotes nuclear localization and activation of FoxO proteins, which—depending on the cellular context—can lead to cell cycle arrest or apoptosis. In endothelial cells (ECs), they further regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxOs exert a tumor-suppressive function by regulating proliferation and survival. We and others have previously shown that FoxOs can regulate these processes via two different mechanisms: by direct binding to forkhead-responsive elements at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here, we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners that might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed transformation/transcription domain-associated protein (TRRAP), a member of multiple histone acetyltransferase complexes, as a novel binding partner of FoxO family proteins. We demonstrate that TRRAP is required to support FoxO3 transactivation and FoxO3-dependent G1 arrest and apoptosis in ECs via transcriptional activation of the cyclin-dependent kinase inhibitor p27\(^{kip1}\) and the proapoptotic B-cell lymphoma 2 family member, BIM. Moreover, FoxO-TRRAP interaction could explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking forkhead-responsive element sequences.}, language = {en} } @article{SchwanLangSchlosseretal.2022, author = {Schwan, Carsten and Lang, Alexander E. and Schlosser, Andreas and Fujita-Becker, Setsuko and AlHaj, Abdulatif and Schr{\"o}der, Rasmus R. and Faix, Jan and Aktories, Klaus and Mannherz, Hans Georg}, title = {Inhibition of Arp2/3 complex after ADP-ribosylation of Arp2 by binary Clostridioides toxins}, series = {Cells}, volume = {11}, journal = {Cells}, number = {22}, issn = {2073-4409}, doi = {10.3390/cells11223661}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297454}, year = {2022}, abstract = {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.}, language = {en} }