title: Formation and removal of poly-ubiquitin chains in the regulation of tumor necrosis factor-induced gene activation and cell death.
abstract: 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.
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kupka
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics* / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D025821:Polyubiquitin / Q000378:metabolism*; D055503:Protein Multimerization; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D048069:Tumor Necrosis Factors; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D010450:Endopeptidases; C582107:OTULIN protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: A20; CYLD; HOIL-1; HOIP; LUBAC; OTULIN; SHARPIN; TNFR1; Ubiquitin; cell death