TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Salzmann, Steffen; Lang, Isabell; Rosenthal, Alevtina; Schäfer, Viktoria; Weisenberger, Daniela; Arana, José Antonio Carmona; Trebing, Johannes; Siegmund, Daniela; Neumann, Manfred; Wajant, Harald

doi:10.4049/jimmunol.1202899

Cited by 15 publications

(18 citation statements)

References 57 publications

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“…Unlike the stimulation of the canonical pathway, which is quite rapid, the non-canonical pathway is gradually activated over several hours, possibly due to the requirement for de novo NIK translation and accumulation. The lysosomal degradation of cIAP1 and TRAF2 by TWEAK impairs NF-κB activation by other cytokines that require these adaptors; thus, TWEAK sensitizes cancer cells to TNFα-induced apoptosis through activation of caspase-8 (8, 18, 61). The cIAPs are thus considered to be negative regulators of the non-canonical NF-κB pathway, through their constitutive effects on NIK degradation.…”

Section: Regulation Of Nf-κb Signaling By Tweakmentioning

confidence: 99%

Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis

et al. 2014

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Mammalian skeletal muscle maintains a robust regenerative capacity throughout life, largely due to the presence of a stem cell population known as “satellite cells” in the muscle milieu. In normal conditions, these cells remain quiescent; they are activated upon injury to become myoblasts, which proliferate extensively and eventually differentiate and fuse to form new multinucleated muscle fibers. Recent findings have identified some of the factors, including the cytokine TNFα-like weak inducer of apoptosis (TWEAK), which govern these cells’ decisions to proliferate, differentiate, or fuse. In this review, we will address the functions of TWEAK, its receptor Fn14, and the associated signal transduction molecule, the cellular inhibitor of apoptosis 1 (cIAP1), in the regulation of myogenesis. TWEAK signaling can activate the canonical NF-κB signaling pathway, which promotes myoblast proliferation and inhibits myogenesis. In addition, TWEAK activates the non-canonical NF-κB pathway, which, in contrast, promotes myogenesis by increasing myoblast fusion. Both pathways are regulated by cIAP1, which is an essential component of downstream signaling mediated by TWEAK and similar cytokines. This review will focus on the seemingly contradictory roles played by TWEAK during muscle regeneration, by highlighting the interplay between the two NF-κB pathways under physiological and pathological conditions. We will also discuss how myogenesis is negatively affected by chronic conditions, which affect homeostasis of the skeletal muscle environment.

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Section: Regulation Of Nf-κb Signaling By Tweakmentioning

confidence: 99%

Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis

et al. 2014

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“…Nevertheless, concomitant removal of c-IAP1/2 and TRAF2/3 likely provides added guarantees that ensure the liberation of NIK and activation of signaling. An additional consequence of TWEAK mediated elimination of TRAF2 and c-IAP proteins is the diminished activation of TNF or CD40L stimulated canonical NF-κB and MAPK signaling (36, 58). Since TNFR1 and CD40 rely on c-IAPs and TRAF2 for the assembly of signaling complex and the activation of the canonical NF-κB and MAPK pathways, TWEAK can negatively impact the signaling downstream of TNFR1 and CD40 by depleting critical E3 ligases and adaptors (25, 36, 58).…”

Section: E3 Ligases and Ubiquitin Linkages In Tweak Signalingmentioning

confidence: 99%

The Role of Ubiquitination in TWEAK-Stimulated Signaling

Vucic¹

2013

Front. Immunol.

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Tumor necrosis factor superfamily ligands and receptors are responsible for development, immunity, and homeostasis of metazoan organisms. Thus, it is not surprising that signals emanating from these receptors are tightly regulated. Binding of TNF-related weak inducer of apoptosis (TWEAK) to its cognate receptor, FN14, triggers the assembly of receptor-associated signaling complex, which allows the activation of canonical and non-canonical nuclear factor kappa B (NF-κB) as well as mitogen-activated protein kinase signaling pathways. Ubiquitin ligases cellular inhibitor of apoptosis 1 and 2 (c-IAP1 and 2) and adaptor proteins TNFR-associated factors 2 and 3 (TRAF2 and TRAF3) are crucial for the regulation of TWEAK signaling as they facilitate the recruitment of distal signaling components including IKK and linear ubiquitin chain assembly complex complexes. At the same time c-IAP1/2, together with TRAF2 and TRAF3, promote constitutive ubiquitination and proteasomal degradation of NF-κB inducing kinase (NIK) – a kinase with critical role in the activation of non-canonical NF-κB signaling. While c-IAP1/2 mediated ubiquitination allows the activation of TWEAK-stimulated canonical NF-κB signaling, these E3 ligases are negative regulators of non-canonical signaling. TWEAK stimulation prompts the recruitment of c-IAP1/2 as well as TRAF2 and TRAF3 to the FN14 signaling complex leading to c-IAP1/2 autoubiquitination and degradation, which stabilizes NIK and allows subsequent phosphorylation of IKKα and partial proteasomal processing of p100 to activate gene expression. Recent studies have revealed that the spatio-temporal pattern of TWEAK-stimulated ubiquitination is a carefully orchestrated process involving several substrates that are modified by different ubiquitin linkages. Understanding the significance of ubiquitination for TWEAK signaling is important for the overall understanding of TWEAK biology and for the design of therapeutics that can be used in the treatment of human pathologies that are driven by TWEAK/FN14 expression and activity.

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“…[9][10][11][12][13][14][15] Accordingly, various scFvGpL and GpL-TNFSF ligand fusion proteins proved to be highly suitable for cellular binding studies and tracer applications. We therefore evaluated whether GpL-tagging is also applicable and useful for conventional antibodies.…”

Section: Resultsmentioning

confidence: 99%

Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princeps luciferase antibody fusion proteins

Kums

Nelke

Rüth

et al. 2017

mAbs

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Cell surface antigen-specific antibodies are of substantial diagnostic and therapeutic importance. The binding properties of such antibodies are usually evaluated by cell-free assays, in particular surface plasmon resonance (SPR) analysis, or flow cytometry. SPR analyses allow the detailed quantitative and dynamic evaluation of the binding properties of antibodies, but need purified, typically recombinantly produced antigens. It can, however, be difficult to produce the required antigen. Furthermore, cellular factors influencing the antigen-antibody interaction are not considered by this method. Flow cytometrybased analyses do not have these limitations, but require elaborated calibration controls for absolute quantification of bound molecules. To overcome the limitations of SRP and flow cytometry in the characterization of cell surface antigen-specific antibodies, we developed Fn14-specific antibody 18D1 as an example of an antibody fusion protein format that includes the luciferase of Gaussia princeps (GpL), which enables very simple and highly sensitive cellular binding studies. We found that GpL-tagging of the C-terminus of the antibody light chain does not affect the interaction of 18D1-IgG1 with its antigen and Fc-gamma receptors (FcgRs). In accordance with this, the GpL (LC-CT) -18D1-IgG1 antibody fusion protein showed basically the same FcgR-dependent agonistic properties as the parental 18D1 antibody. Similar results were obtained with isotype switch variants of 18D1 and antibodies specific for CD95, LTbR and CD40. In sum, we demonstrate that antibody GpL fusion proteins are easily manageable and versatile tools for the characterization of cell surface antigen-antibody interactions that have the potential to considerably extend the instrumentarium for the evaluation of antibodies.Abbreviations: GpL, Gaussia princeps luciferase; FcgR, Fc-gamma receptor; Fn14, fibroblast growth factor-inducible 14; TWEAK, tumor necrosis factor (TNF)-related weak inducer of apoptosis

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TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Cited by 15 publications

References 57 publications

Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis

Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis

The Role of Ubiquitination in TWEAK-Stimulated Signaling

Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princeps luciferase antibody fusion proteins

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