LUBAC-mediated linear ubiquitination in tissue homeostasis and disease

In addition to its role in the ubiquitin-proteasome system of protein degradation, polyubiquitination is involved in the regulation of intracellular events. Depending on the type of ubiquitin-ubiquitin linkage used, polyubiquitin can assume several types of structures. The spatiotemporal dynamics of polyubiquitin involve multiple adaptor proteins and induce different downstream outputs. Linear ubiquitination, in which the N-terminal methionine on the acceptor ubiquitin serves as the site for ubiquitin-ubiquitin conjugation, is a rare and atypical type of polyubiquitin modification. The production of linear ubiquitin chains is dependent on various external inflammatory stimuli and leads to the transient activation of the downstream NF-κB signalling pathway. This in turn suppresses extrinsic programmed cell death signals and protects cells from activation-induced cell death under inflammatory conditions. Recent evidence has revealed the role of linear ubiquitination in various biological processes under both physiological and pathological conditions. This led us to propose that linear ubiquitination may be pivotal in the 'inflammatory adaptation' of cells, and consequently in tissue homeostasis and inflammatory disease. In this review, we focused on the physiological and pathophysiological roles of linear ubiquitination in vivo in response to a changing inflammatory microenvironment.