@article{SiegmundZaitsevaWajant2023,
  author    = {Siegmund, Daniela and Zaitseva, Olena and Wajant, Harald},
  title     = {Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {11},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2023.1267837},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354304},
  year      = {2023},
  abstract  = {Tumor necrosis factor (TNF) receptor 1 (TNFR1), TNFR2 and fibroblast growth factor-inducible 14 (Fn14) belong to the TNF receptor superfamily (TNFRSF). From a structural point of view, TNFR1 is a prototypic death domain (DD)-containing receptor. In contrast to other prominent death receptors, such as CD95/Fas and the two TRAIL death receptors DR4 and DR5, however, liganded TNFR1 does not instruct the formation of a plasma membrane-associated death inducing signaling complex converting procaspase-8 into highly active mature heterotetrameric caspase-8 molecules. Instead, liganded TNFR1 recruits the DD-containing cytoplasmic signaling proteins TRADD and RIPK1 and empowers these proteins to trigger cell death signaling by cytosolic complexes after their release from the TNFR1 signaling complex. The activity and quality (apoptosis versus necroptosis) of TNF-induced cell death signaling is controlled by caspase-8, the caspase-8 regulatory FLIP proteins, TRAF2, RIPK1 and the RIPK1-ubiquitinating E3 ligases cIAP1 and cIAP2. TNFR2 and Fn14 efficiently recruit TRAF2 along with the TRAF2 binding partners cIAP1 and cIAP2 and can thereby limit the availability of these molecules for other TRAF2/cIAP1/2-utilizing proteins including TNFR1. Accordingly, at the cellular level engagement of TNFR2 or Fn14 inhibits TNFR1-induced RIPK1-mediated effects reaching from activation of the classical NFκB pathway to induction of apoptosis and necroptosis. In this review, we summarize the effects of TNFR2- and Fn14-mediated depletion of TRAF2 and the cIAP1/2 on TNFR1 signaling at the molecular level and discuss the consequences this has in vivo.},
  language  = {en}
}
@phdthesis{Roos2009,
  author    = {Roos, Claudia},
  title     = {Characterization of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced signaling pathways},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45295},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {TWEAK ist ein typischer Vertreter der TNF Ligandenfamilie. TWEAK wird als Typ II Transmembranprotein exprimiert, kann jedoch durch proteolytische Prozessierung auch als l{\"o}sliches Protein freigesetzt werden. In dieser Arbeit wird gezeigt, dass oligomerisiertes TWEAK in Hinblick auf die Aktivierung des klassischen NF\&\#954;B Signalweges deutlich aktiver ist als l{\"o}sliches, trimeres TWEAK. Jedoch sind beide TWEAK-Varianten in der Lage, die Depletion von TRAF2 und die Prozessierung von p100, beides Kennzeichen f{\"u}r die Aktivierung des alternativen NF\&\#954;B Signalweges, zu induzieren. Ebenso wie andere l{\"o}sliche TNF-Liganden, die ihren entsprechenden Rezeptor nur schwach aktivieren, erlangt l{\"o}sliches TWEAK durch Oligomerisierung vergleichbare Aktivit{\"a}t zum membrangebundenen Liganden. TRAF2 spielt eine Schl{\"u}sselrolle in der TWEAK-vermittelten NF\&\#954;B Aktivierung. Durch Depletion oder Degradation von TRAF2 f{\"a}llt die Entscheidung, ob lediglich der alternative oder beide, der klassische und der alternative NF\&\#954;B Signalweg aktiviert werden. Die Blockade des TWEAK-Rezeptors Fn14 inhibiert die Aktivierung der NF\&\#954;B Signalwege, ungeachtet welche Form von TWEAK zur Stimulation genutzt wird. Das weist darauf hin, dass die unterschiedlichen Aktivit{\"a}ten der beiden TWEAK-Varianten in der Induktion des klassischen und alternativen NF\&\#954;B Signalweges nicht durch die Nutzung verschiedener Rezeptoren verursacht sind. Damit wird in dieser Arbeit anhand von TWEAK zum ersten mal gezeigt, dass ein TNF Ligand in unterschiedlichen Varianten qualitativ unterschiedliche Aktivit{\"a}ten des entsprechenden TNF Rezeptors ausl{\"o}st.},
  subject      = {Tumor-Nekrose-Faktor},
  language  = {en}
}
@article{MuellerSienerthDietzHoltzetal.2011,
  author    = {M{\"u}ller-Sienerth, Nicole and Dietz, Lena and Holtz, Philipp and Kapp, Markus and Grigoleit, G{\"o}tz Ulrich and Schmuck, Carsten and Wajant, Harald and Siegmund, Daniela},
  title     = {SMAC Mimetic BV6 Induces Cell Death in Monocytes and Maturation of Monocyte-Derived Dendritic Cells},
  series = {PLoS ONE},
  volume    = {6},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0021556},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142415},
  pages     = {e21556},
  year      = {2011},
  abstract  = {Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NF kappa B system and TNF signaling. In view of the overwhelming importance of the NF kappa B transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings: BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NF kappa B pathway, but it also diminished the stronger NF kappa B-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12. Significance: The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies.},
  language  = {en}
}
@article{KreckelAnanySiegmundetal.2019,
  author    = {Kreckel, Jennifer and Anany, Mohammed A. and Siegmund, Daniela and Wajant, Harald},
  title     = {TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  number    = {2024},
  doi       = {10.3389/fimmu.2019.02024},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201822},
  year      = {2019},
  abstract  = {Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.},
  language  = {en}
}