title: Linear ubiquitination in NF-κB signaling and inflammation: What we do understand and what we do not.
abstract: 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.
authors.affiliation: Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Verhelst
authors.forename: Lynn
authors.initials: L
authors.lastname: Verstrepen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carpentier
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D025801:Ubiquitin