title: Linear ubiquitination-mediated NF-κB regulation and its related disorders.
abstract: Ubiquitination is a post-translational modification involved in the regulation of a broad variety of cellular functions, such as protein degradation and signal transduction, including nuclear factor-κB (NF-κB) signalling. NF-κB is crucial for inflammatory and immune responses, and aberrant NF-κB signalling is implicated in multiple disorders. We found that linear ubiquitin chain assembly complex (LUBAC), composed of HOIL-1L, HOIP and SHARPIN, generates a novel type of Met1 (M1)-linked linear polyubiquitin chain and specifically regulates the canonical NF-κB pathway. Moreover, specific deubiquitinases, such as CYLD, A20 (TNFAIP3) and OTULIN/gumby, inhibit LUBAC-induced NF-κB activation by different molecular mechanisms, and several M1-linked ubiquitin-specific binding domains have been structurally defined. LUBAC and these linear ubiquitination-regulating factors contribute to immune and inflammatory processes and apoptosis. Functional impairments of these factors are correlated with multiple disorders, including autoinflammation, immunodeficiencies, dermatitis, B-cell lymphomas and Parkinson's disease. This review summarizes the molecular basis and the pathophysiological implications of the linear ubiquitination-mediated NF-κB activation pathway regulation by LUBAC.
authors: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8912, Japan.
authors: Fuminori
authors: F
authors: Tokunaga
mesh_terms: D056704:Adaptive Immunity; D017209:Apoptosis; D063646:Carcinogenesis / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D010300:Parkinson Disease / Q000276:immunology / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D025801:Ubiquitin; D025821:Polyubiquitin; D043743:Ubiquitin-Protein Ligase Complexes
keywords: LUBAC; NF-κB; immune response; inflammation; ubiquitin