@article{JarickBertscheStahletal.2018,
  author    = {Jarick, Marcel and Bertsche, Ute and Stahl, Mark and Schultz, Daniel and Methling, Karen and Lalk, Michael and Stigloher, Christian and Steger, Mirco and Schlosser, Andreas and Ohlsen, Knut},
  title     = {The serine/threonine kinase Stk and the phosphatase Stp regulate cell wall synthesis in Staphylococcus aureus},
  series = {Scientific Reports},
  volume    = {8},
  journal   = {Scientific Reports},
  number    = {13693},
  doi       = {10.1038/s41598-018-32109-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177333},
  year      = {2018},
  abstract  = {The cell wall synthesis pathway producing peptidoglycan is a highly coordinated and tightly regulated process. Although the major components of bacterial cell walls have been known for decades, the complex regulatory network controlling peptidoglycan synthesis and many details of the cell division machinery are not well understood. The eukaryotic-like serine/threonine kinase Stk and the cognate phosphatase Stp play an important role in cell wall biosynthesis and drug resistance in S. aureus. We show that stp deletion has a pronounced impact on cell wall synthesis. Deletion of stp leads to a thicker cell wall and decreases susceptibility to lysostaphin. Stationary phase Δstp cells accumulate peptidoglycan precursors and incorporate higher amounts of incomplete muropeptides with non-glycine, monoglycine and monoalanine interpeptide bridges into the cell wall. In line with this cell wall phenotype, we demonstrate that the lipid II:glycine glycyltransferase FemX can be phosphorylated by the Ser/Thr kinase Stk in vitro. Mass spectrometric analyses identify Thr32, Thr36 and Ser415 as phosphoacceptors. The cognate phosphatase Stp dephosphorylates these phosphorylation sites. Moreover, Stk interacts with FemA and FemB, but is unable to phosphorylate them. Our data indicate that Stk and Stp modulate cell wall synthesis and cell division at several levels.},
  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}
}
@article{BruennertSeupelGoyaletal.2023,
  author    = {Br{\"u}nnert, Daniela and Seupel, Raina and Goyal, Pankaj and Bach, Matthias and Schraud, Heike and Kirner, Stefanie and K{\"o}ster, Eva and Feineis, Doris and Bargou, Ralf C. and Schlosser, Andreas and Bringmann, Gerhard and Chatterjee, Manik},
  title     = {Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate},
  series = {Pharmaceuticals},
  volume    = {16},
  journal   = {Pharmaceuticals},
  number    = {8},
  issn      = {1424-8247},
  doi       = {10.3390/ph16081181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362887},
  year      = {2023},
  abstract  = {The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.},
  language  = {en}
}
@article{ElMeseryRosenthalRauertWunderlichetal.2019,
  author    = {El-Mesery, Mohamed and Rosenthal, Tina and Rauert-Wunderlich, Hilka and Schreder, Martin and St{\"u}hmer, Thorsten and Leich, Ellen and Schlosser, Andreas and Ehrenschwender, Martin and Wajant, Harald and Siegmund, Daniela},
  title     = {The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death},
  series = {Cell Death \& Disease},
  volume    = {10},
  journal   = {Cell Death \& Disease},
  doi       = {10.1038/s41419-019-1860-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226666},
  year      = {2019},
  abstract  = {The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.},
  language  = {en}
}