Trends in Biochemical Sciences
ReviewLinear ubiquitination: a newly discovered regulator of cell signalling
Section snippets
Ubiquitin system
Post-translational modifications regulate and fine tune signals induced by extracellular and intrinsic stimuli. Ubiquitination, along with phosphorylation, are arguably the two best-studied and perhaps main regulatory modifications. Phosphorylation is the covalent attachment of a phosphoryl group to a serine, threonine, or tyrosine residue of a target protein, thereby altering its electrostatic properties and allowing recruitment of downstream proteins and/or a change in activity.
Diversity of inter-ubiquitin linkages
How are differently linked di-ubiquitins different from each other? Each of the eight di-ubiquitin linkage types results in a distinct, unique overall structure with continuous surfaces and relative topologies between the two individual ubiquitin moieties. These structural differences are decoded by ubiquitin receptors that interact with high affinity with certain di-ubiquitin linkages and not others, thereby translating structural information into specific functions [5]. It is currently
Different classes of E3s act via distinct mechanisms
E2s are generally thought to determine linkage specificity, whereas E3s are thought to confer substrate specificity by facilitating the interaction between a particular substrate and an E2 [13]. However, although some E2s possess unique linkage specificity, others – including the UbcH5 family – are rather promiscuous and contribute to the generation of various ubiquitin linkages [14]. Based on their structure and function, E3s can be classified into HECT (homology to E6AP C terminus), RING
LUBAC: a novel RBR that promotes linear ubiquitin linkages
Heme-oxidised iron-responsive element-binding protein 2 (IRP2) ubiquitin ligase-1 [HOIL-1; also called RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1)] and HOIL-1-interacting protein (HOIP; also known as RNF31) are members of the RBR family. These two proteins have recently entered the spotlight because they form part of the LUBAC, a 600-kDa E3 complex capable of forming linear ubiquitin linkages, [20]. SH3 and multiple ankyrin repeat domains protein (SHANK)-associated RBCK1
Role of linear ubiquitination in TNF receptor 1 (TNFR1) signalling
The physiological function of LUBAC and linear ubiquitin linkages remained unclear for several years. It was initially proposed that M1 ubiquitination triggers proteasomal degradation [20]. Subsequently, however, it was discovered that LUBAC is implicated in various signalling pathways including those triggered by TNF, IL-1β, CD40 ligand (CD40L), various Toll-like receptors (TLRs), and NOD2 (nucleotide-binding oligomerisation domain-containing protein 2) 21, 23, 24, 25, 29, 30, 31 (Figure 5).
Implication of linear ubiquitination in other signalling pathways
Although the function of LUBAC is best characterised in TNFR1 signalling, it has also been implicated in a variety of other signalling pathways. CD40 is a TNFR superfamily member expressed on the surface of antigen-presenting cells and is required for various crucial steps in achieving adaptive immunity. Stimulation of CD40 by CD40L on B cells results in activation of MAPKs and canonical and noncanonical NF-κB signalling. LUBAC also forms part of the native CD40-RSC [21]. Interestingly,
Concluding remarks
It came as a surprise that LUBAC is a bona fide component of the TNF-RSC and that it functions to place M1 linkages on key signalling hubs, modifying the output of many different signalling pathways. Yet, it establishes LUBAC and the M1-ubiquitin linkage as crucial components in the cellular signalling repertoire. For most signalling complexes and pathways it remains to be determined how exactly LUBAC influences them, which factors are targeted by LUBAC, and how their function is thereby
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