The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation

Hrdinka, Matouš; Gyrd‐Hansen, Mads

doi:10.1016/j.molcel.2017.09.001

Cited by 118 publications

(132 citation statements)

References 128 publications

(243 reference statements)

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“…Reduction in LUBAC levels, primarily in HOIP and SHARPIN, has also been reported in fibroblasts from three different ORAS patients (Zhou et al, 2016). This suggests that distinct pools of LUBAC-DUB complexes may exist (Hrdinka & Gyrd-Hansen, 2017). This striking cell type-specific effect on LUBAC suggests that the phenotype of different cell types upon loss of OTULIN may depend on their LUBAC status.…”

Section: Discussionmentioning

confidence: 68%

“…This is evident from clinical genetic studies (Boisson et al, 2012(Boisson et al, , 2015Damgaard et al, 2016;Zhou et al, 2016) and numerous mouse studies (reviewed in Hrdinka & Gyrd-Hansen, 2017). This is evident from clinical genetic studies (Boisson et al, 2012(Boisson et al, , 2015Damgaard et al, 2016;Zhou et al, 2016) and numerous mouse studies (reviewed in Hrdinka & Gyrd-Hansen, 2017).…”

Section: Discussionmentioning

confidence: 97%

“…K48-linked chains mediate timed degradation of the inhibitor of jB (IjB) proteins while non-degradative chains, including K63-and M1-linked chains, serve as recruitment and activation platforms in signalling complexes formed after engagement of pattern recognition receptors (PRRs) and cytokine receptors, e.g. K63 and M1 Ub linkages can occur in the same Ub polymers (Emmerich et al, 2013), facilitating TAK1 and IKK co-localisation and cross-activation (reviewed in Hrdinka & Gyrd-Hansen 2017). Receptor stimulation, for example of TNF-R1, triggers assembly of multi-protein receptor signalling complexes (RSCs) that include a host of E3 Ub ligases, including TNF receptor-associated factors (TRAFs), inhibitor of apoptosis proteins (IAPs) and the linear Ub chain assembly complex (LUBAC).…”

Section: Introductionmentioning

confidence: 99%

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OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

et al. 2019

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The deubiquitinase OTULIN removes methionine‐1 (M1)‐linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF‐driven inflammation in OTULIN‐related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1‐linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN‐Gly281Arg mutation leads to reduced activity and stability in vitro and in cells. In contrast to OTULIN‐deficient monocytes, in which TNF signalling and NF‐κB activation are increased, loss of OTULIN in patient‐derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF. Interestingly, both patient‐derived fibroblasts and OTULIN‐deficient monocytes are sensitised to certain types of TNF‐induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS. Together, our data suggest that ORAS pathogenesis involves hyper‐inflammatory immune cells and TNF‐induced death of both leukocytes and non‐haematopoietic cells.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

et al. 2019

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“…Linear chains form through the covalent attachment of the N-terminal methionine of the first Ub to the α- carboxyl group on Glycine-76 of the next Ub that is to be added [29]. This has been extensively reviewed elsewhere [30] and is in contrast to the modifications in which Ub can form poly-Ub chains via its seven lysine residues. Downstream of TNFR, NEMO has the capacity to be targeted and modified via linear ubiquitination by linear Ub chain assembly complex (LUBAC) [28], which is essential for the activation of NF-κB [31].…”

Section: Introductionmentioning

confidence: 99%

Modulating inflammation through the negative regulation of NF-κB signaling

Rothschild

McDaniel

Ringel‐Scaia

et al. 2018

Journal of Leukocyte Biology

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Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto-inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies.

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“…All of these proteins have been implicated in regulating the signaling pathways that involve linear ubiquitination (Fig. A–B) .…”

Section: Linear Ubiquitin Chain‐specific Binding Domains and Their Bimentioning

confidence: 99%

Linear ubiquitin chain‐binding domains

2018

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Ubiquitin modification (ubiquitination) of target proteins can vary with respect to chain lengths, linkage type, and chain forms, such as homologous, mixed, and branched ubiquitin chains. Thus, ubiquitination can generate multiple unique surfaces on a target protein substrate. Ubiquitinbinding domains (UBDs) recognize ubiquitinated substrates, by specifically binding to these unique surfaces, modulate the formation of cellular signaling complexes and regulate downstream signaling cascades. Among the eight different homotypic chain types, Met1-linked (also termed linear) chains are the only chains in which linkage occurs on a non-Lys residue of ubiquitin. Linear ubiquitin chains have been implicated in immune responses, cell death and autophagy, and several UBDs -specific for linear ubiquitin chains -have been identified. In this review, we describe the main principles of ubiquitin recognition by UBDs, focusing on linear ubiquitin chains and their roles in biology.

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The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation

Cited by 118 publications

References 128 publications

OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

Modulating inflammation through the negative regulation of NF-κB signaling

Linear ubiquitin chain‐binding domains

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