Abstract
SummaryLinear ubiquitination is a post‐translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types.
Highlights
Ubiquitination is a post-translational protein modification that consists in the attachment of one or more ubiquitins to a targetThis article is part of a series of reviews covering Ubiquitination in the Immune System appearing in Volume 266 of Immunological Reviews protein
linear ubiquitin chain assembly complex (LUBAC) consists of two really interesting new gene (RING)-between-RING (RBR) E3s, which are heme-oxidized iron-responsive element-binding protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) and HOIL-1-interacting protein (HOIP), and a third component which is the SH3 and multiple ankyrin repeat domains protein (SHANK)-associated RBCK1 homology (RH)domain-interacting protein (SHARPIN) [11,12,13]
A complex formed by TRIF, TNF receptor-associated death domain (TRADD), TRAF6, the E3 ligase Pellino-1, and receptor-interacting protein kinase 1 (RIPK1) recruits the IKK and TAB/TAK complexes resulting in nuclear factor-jB (NF-jB) and mitogen-activated protein kinases (MAPKs) activation [37, 38], whereas a complex composed of TRIF, TRAF3, tank-binding kinase 1 (TBK1)/IKKe results in phosphorylation of the transcription factors interferon regulatory factor 3 (IRF3) and IRF7 and consequent type-I IFN production [36]
Summary
Ubiquitination ( known as ubiquitylation or ubiquitinylation) is a post-translational protein modification that consists in the attachment of one or more ubiquitins to a target. LUBAC consists of two RING-between-RING (RBR) E3s, which are heme-oxidized iron-responsive element-binding protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) and HOIL-1-interacting protein (HOIP), and a third component which is the SH3 and multiple ankyrin repeat domains protein (SHANK)-associated RBCK1 homology (RH)domain-interacting protein (SHARPIN) [11,12,13] Both HOIL-1 and HOIP bear an RBR domain, HOIP is the catalytically active subunit of LUBAC, since LUBAC containing inactive HOIL-1 can still produce linear ubiquitin chains [6]. The C-terminus of HOIP harbors an RBR domain and a linear ubiquitin chain-determining domain Together, they represent the minimal catalytic core capable of forming Met1-linked di-ubiquitin (Met1-di-Ub) [14]. The specificity for Met1-di-Ub formation by HOIP is coordinated between its catalytic core and its interaction with the two ubiquitin moieties to be linked
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