RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation.

Maria Feoktistova,Amir S Yazdi,Roman Makarov,Diana Panayotova-Dimitrova

doi:10.3390/ijms222212459

Maria Feoktistova, Amir S Yazdi + Show 2 more

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https://doi.org/10.3390/ijms222212459

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Abstract

TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.

Highlights

Tumor necrosis factor (TNF) is a proinflammatory cytokine of critical importance for maintaining tissue homeostasis. [1]
We addressed the function of RIPK1 and TNFR1-associated death domain (TRADD) in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines, respectively
In both conditions, the control HeLa cells were sensitive to TNFinduced apoptosis, which was completely blocked by zVAD-fmk (Figure 1A, panels 5 and 6)

Summary

Introduction

Tumor necrosis factor (TNF) is a proinflammatory cytokine of critical importance for maintaining tissue homeostasis. [1]. Tumor necrosis factor (TNF) is a proinflammatory cytokine of critical importance for maintaining tissue homeostasis. Through binding to the surface receptors TNF receptor. 1 (TNFR1) and TNF receptor 2 (TNFR2), TNF can initiate intracellular signaling pathways that regulate cell death and survival as well as cellular differentiation, proliferation, and immune responses. Upon activation of TNFR1, an intracellular protein complex, known as complex I, which contains receptor interacting protein 1 (RIPK1), TNFR1-associated death domain (TRADD), and other signaling molecules, is rapidly formed and activates the induction of inflammatory and survival genes. Results in synthesis inhibition of a short living protein cFLIP, which is a known inhibitor of caspase-8. This leads to formation of the complex IIa and subsequent apoptosis [3]

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