The Linear Ubiquitin Chain Assembly Complex (LUBAC) Forms Part of the TNF-R1 Signalling Complex and Is Required for Effective TNF-Induced Gene Induction and Prevents TNF-Induced Apoptosis

摘要

In 1974, a 76 residue polypeptide was isolated from bovine thymus during the isolation of thymopoietin and termed ubiquitin [7, 24]. This small protein was later to become an important player not only for cellular protein degradation processes but also in signal transduction induced by TNF-receptor 1 (TNF-R1) as well as many other ligand-receptor systems. Ubiquitin is a highly conserved protein that can be covalently attached to substrate proteins to regulate a wide variety of biological processes such as endocytic trafficking, NF-kappaB signalling, gene expression, DNA repair, and apoptosis [5]. Generally, ubiquitin is attached via its C-terminal glycine residue to the e-amino group of a substrate lysine (K) residue. The transfer of ubiquitin to a substrate or a pre-existing ubiquitin chain is mediated by the sequential action of three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). Ubiquitin itself has seven lysine residues and one terminal amino group, all of which can be used to attach additional ubiquitin molecules, producing eight types of poly-ubiquitin chains [12, 14]. Based on recent studies it now becomes clear how these different types of ubiquitin chains are capable of mediating different intracellular signals [6, 15, 25, 29]. Depending on the lysine residue, which serves as acceptor for further attachment of ubiquitin molecules, differently linked polyubiquitin chains adopt distinct structures that enable interactions with linkage-specific ubiquitin receptors. The resulting collection of heterogeneous recognition patterns can be bound by a variety of ubiquitin-binding domains (UBDs) present in the receptor proteins.