The Emerging Role of Linear Ubiquitination in Cell Signaling

Linear ubiquitin chains transmit signals that are induced by diverse stimuli and regulate cell activation and death. To ensure appropriate responses of cells to external stimuli, the intracellular events that initiate these reactions must be tightly controlled. Different mechanisms ensure this regulation. One possibility involves the attachment of regulatory elements onto components of signal-initiating complexes. One form of modification is the attachment of particular cellular proteins, an example of which is the covalent coupling of ubiquitin to a target protein by a specialized enzymatic system, a process called ubiquitination. Such modifications have different functions, ranging from the recruitment of other binding partners to the activation or inactivation of the substrate. Ubiquitination can attach single ubiquitin molecules and chains consisting of several ubiquitin moieties to target proteins. Depending on how the single ubiquitin units within these chains are linked, their structure and consequently their function differ. It was originally thought that only seven different types of polyubiquitin chains could be generated, based on the seven lysine residues in ubiquitin that serve as internal linkage points. However, a protein complex called linear ubiquitin chain assembly complex (LUBAC) was discovered that uses the N terminus of ubiquitin, rather than an internal lysine, thereby forming linear or M1-linked ubiquitin chains. LUBAC and linear ubiquitin chains are important for transmitting signals induced by diverse stimuli that regulate cell activation and death. In this Review, which contains two figures, one table, and 105 references, we discuss the functional role of LUBAC and the linear ubiquitin chains it generates, and we provide an outlook on promising future research directions. The covalent attachment of ubiquitin molecules to target proteins is a posttranslational modification that is involved not only in signaling processes leading to protein degradation but also in those resulting in activation, proliferation, and cell death. Ubiquitination is a versatile regulation mechanism: In addition to single ubiquitin molecules, chains consisting of several ubiquitin moieties can also be attached to target proteins. The functional outcome of polyubiquitination depends on the lysine residue within ubiquitin that is used for chain elongation. The reason for this is that the particular linkage between two ubiquitin moieties through a specific lysine residue of one ubiquitin and the C terminus of the other ubiquitin creates a unique binding surface that is specifically recognized by specialized ubiquitin-binding domains. New evidence indicates that besides the seven internal lysine residues of ubiquitin, the N terminus of ubiquitin can also be used as an attachment point, thereby generating linear or M1-linked polyubiquitin chains. An E3 complex consisting of HOIL-1, HOIP, and Sharpin specifically generates such M1-linked ubiquitin chains in the context of various cellular signaling pathways that regulate cell activation and death, and it was named linear ubiquitin chain assembly complex (LUBAC). In this Review, we focus on the biochemistry and physiological role of linear ubiquitin chains generated by LUBAC. We summarize the function of linear ubiquitin chains in signaling pathways downstream of diverse cellular signaling events and provide an outlook on promising future directions of research.