Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.
Biochem Pharmacol. 2011 Nov 1;82(9):1057-65. doi: 10.1016/j.bcp.2011.07.066. Epub 2011 Jul 20.
Despite its small size, ubiquitin is one of the most versatile signaling molecules in the cell and affects distinct cellular processes. It forms the building block of a repertoire of posttranslational modifications of cellular proteins, ranging from the attachment of a single ubiquitin to ubiquitin chains of different linkage. Proteins that contain ubiquitin chain-specific ubiquitin-binding domains recognize different types of ubiquitination and determine the mode of signaling of modified proteins. Polyubiquitin chains were thought to be formed only by the conjugation of the ubiquitin C-terminal Gly to one of the seven internal Lys residues of another ubiquitin. However, the C-terminal Gly was recently shown to also link to the N-terminus of another ubiquitin to form head-to-tail polyubiquitin chains, which is referred to as linear ubiquitination. These linear linkages can be assembled and conjugated to another protein by an E3 ligase complex known as LUBAC, and are recognized by a particular ubiquitin-binding domain known as UBAN. Both have been implicated in the regulation of TNF-induced NF-κB signaling, which induces the expression of a wide range of proteins that mediate many biological processes including inflammation and cell survival. We discuss the molecular players and mechanisms that determine the specificity and outcome of linear ubiquitination in NF-κB signaling, as well as future directions and challenges ahead.
尽管它的体积很小，但泛素是细胞中用途最广泛的信号分子之一，影响着不同的细胞过程。它形成了细胞蛋白的一系列翻译后修饰的构建块，范围从单个泛素的附着到不同连接的泛素链。含有泛素链特异性泛素结合结构域的蛋白质识别不同类型的泛素化，并确定修饰蛋白的信号转导方式。多泛素链被认为仅通过泛素 C 末端 Gly 与另一个泛素的七个内部 Lys 残基之一的缀合形成。然而，最近发现 C 末端 Gly 也可以与另一个泛素的 N 末端连接，形成从头至尾的多泛素链，这被称为线性泛素化。这些线性连接可以通过称为 LUBAC 的 E3 连接酶复合物组装并连接到另一个蛋白质上，并被称为 UBAN 的特定泛素结合结构域识别。两者都被认为参与了 TNF 诱导的 NF-κB 信号转导的调节，该信号转导诱导表达广泛的蛋白质，介导许多生物学过程，包括炎症和细胞存活。我们讨论了决定线性泛素化在 NF-κB 信号转导中的特异性和结果的分子参与者和机制，以及未来的方向和挑战。
