Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death

Tumor necrosis factor (TNF) is a potent cytokine known for its involvement in inflammation, repression of tumorigenesis and activation of immune cells. Consequently, accurate regulation of the TNF signaling pathway is crucial for preventing the potent noxious effects of TNF. These pathological conditions include chronic inflammation, septic shock, cachexia and cancer. The TNF signaling cascade utilizes a complex network of post‐translational modifications to control the cellular response following its activation. Next to phosphorylation, the ubiquitination of signaling complex components is probably the most important modification. This process is mediated by a specialist class of enzymes, the ubiquitin ligases. Equally important is the class of dedicated ubiquitin‐specific proteases, the deubiquitinases. Together with ubiquitin binding proteins, this ubiquitination–deubiquitination system enables the dynamics of signaling complexes. In TNF signaling, these dynamics translate into the precise regulation of the induction of gene activation or cell death. Here, we review and discuss current knowledge of TNF signaling regulation by the ubiquitin system. Stimulation of TNFR1 promotes diverse cell responses, varying from gene activatory signaling to induction of cell death. The assembly of the TNFR1 signaling complex requires ubiquitination mediated by cIAP1/2 and LUBAC. In turn, LUBAC is functionally linked to the deubiquitinases CYLD, OTULIN and A20. In this review we summarize and discuss recent findings on the regulation of TNFR1 signaling.