Intracellular regulation of TNF activity in health and disease.
Tumor Necrosis Factor alpha (TNFα, TNF) is a key mediator and regulator of mammalian immune responses in healthy organisms and in diseased conditions. TNF governs development of the immune system, cell survival signaling pathways, proliferation and regulates metabolic processes. Whereas TNF-induced NF-κB and MAP pro-survival kinase activities constitute its major biochemical functions, TNF can also stimulate cell death in certain pathological situations. TNF-induced signal transduction pathways are tightly regulated through ubiquitination and phosphorylation of molecules partaking in all TNF-dependent membrane-associated and intracellular protein signaling complexes. Deregulated TNF signaling in individuals carrying naturally occurring genetic mutations in proteins that mediate TNF signaling, or in corresponding genetically modified animal models, results in severe pathologies. In this review we will describe the current knowledge of TNF signaling and its relevance for human health.
Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA.
Eugene
E
Varfolomeev
Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: domagoj@gene.com.
Domagoj
D
Vucic
D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
Apoptosis; NF-kB; Necroptosis; RIP kinases; TNF; Ubiquitin