Abstract
Ubiquitination now ranks with phosphorylation as one of the best-studied post-translational modifications of proteins with broad regulatory roles across all of biology. Ubiquitination usually involves the addition of ubiquitin chains to target protein molecules, and these may be of eight different types, seven of which involve the linkage of one of the seven internal lysine (K) residues in one ubiquitin molecule to the carboxy-terminal diglycine of the next. In the eighth, the so-called linear ubiquitin chains, the linkage is between the amino-terminal amino group of methionine on a ubiquitin that is conjugated with a target protein and the carboxy-terminal carboxy group of the incoming ubiquitin. Physiological roles are well established for K48-linked chains, which are essential for signaling proteasomal degradation of proteins, and for K63-linked chains, which play a part in recruitment of DNA repair enzymes, cell signaling and endocytosis. We focus here on linear ubiquitin chains, how they are assembled, and how three different avenues of research have indicated physiological roles for linear ubiquitination in innate and adaptive immunity and suppression of inflammation.
Highlights
Ubiquitination ranks with phosphorylation as one of the best-studied post-translational modifications of proteins with broad regulatory roles across all of biology
We review what is known about the process by which linear ubiquitin chains are assembled, and how they contribute to tumor necrosis factor (TNF) receptor 1 (TNFR1) signaling
The combination of recombinant SHARPIN and HOIL-1 cannot generate linear ubiquitin chains in vitro, whereas recombinant HOIP together with HOIL-1 or SHARPIN can; overexpression of these combinations is capable of activating NF-kB, one of the key transcription factors activated by TNF [19,20,21]. This is in line with experiments showing that, despite the fact that HOIL-1 and HOIP both contain an RING (IBR)-RING (RBR) domain (Figure 1), it is the RBR of HOIP that mediates the formation of the linear ubiquitin linkage in these different complexes because the intact RBR of HOIP, but not of HOIL-1, is required for linear ubiquitin chain assembly complex (LUBAC) activity [15]
Summary
Ubiquitination ranks with phosphorylation as one of the best-studied post-translational modifications of proteins with broad regulatory roles across all of biology. This is in line with experiments showing that, despite the fact that HOIL-1 and HOIP both contain an RBR domain (Figure 1), it is the RBR of HOIP that mediates the formation of the linear ubiquitin linkage in these different complexes because the intact RBR of HOIP, but not of HOIL-1, is required for LUBAC activity [15].
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