LUBAC-mediated linear ubiquitination in tissue homeostasis and disease

Abstract

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 spatio-temporal 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 signaling 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.

MALT1 substrate cleavage: what is it good for?

“…While A20 and CYLD counteract multiple NF-κB signaling pathways, the MALT1 substrate HOIL-1 is an integral subunit of LUBAC, which drives NF-κB in response to pro-inflammatory and innate immune stimulation ( 64 ). Like other MALT1 substrates, HOIL-1 is cleaved in antigen-stimulated lymphocytes and in malignant ABC DLBCL cells ( 44 , 65 , 66 ).…”

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

“…The LUBAC assembles ubiquitin chains in which ubiquitin is linked to the amino-terminal methionine at position 1 (M1) of another ubiquitin (referred to as ‘linear’ or ‘M1-linked’ ubiquitin chains). LUBAC and M1-linked polyubiquitin regulate multiple signaling pathways, the best characterized of which is the NF-kB pathway, which controls immune responses, inflammation and cell survival [ 135 ].…”

Lipopolysaccharide Regulates the Macrophage RNA-Binding Proteome

“…8 There T h i s c o n t e n t i s are many levels of post-transcriptional regulation of the TLR signaling cascade, including complex formation with activatory and inhibitory proteins, 9 changes in protein localization, 10 and post-translational modifications such as phosphorylation 11,12 or ubiquitination. 13 Accumulating experimental evidence points to RNA binding as an emerging regulatory checkpoint, emphasizing the importance of RNA-binding proteins (RBPs). 14 One dimension of RNA regulation involves overseeing posttranscriptional control of gene expression, ultimately influencing protein production during inflammatory responses.…”

“…In the case of TLR4, signaling is primarily accomplished via MyD88 in the plasma membrane activating a strong initial release of pro-inflammatory cytokines; further down the line endocytosis of the receptor leads to signaling through TRIF and subsequent production of type I IFN to accumulate more immune cells to the site of infection . There are many levels of post-transcriptional regulation of the TLR signaling cascade, including complex formation with activatory and inhibitory proteins, changes in protein localization, and post-translational modifications such as phosphorylation , or ubiquitination . Accumulating experimental evidence points to RNA binding as an emerging regulatory checkpoint, emphasizing the importance of RNA-binding proteins (RBPs) .…”