Molecular basis for specificity of the Met1-linked polyubiquitin signal

Elliott, P.R.

doi:10.1042/bst20160227

Cited by 21 publications

(21 citation statements)

References 148 publications

(232 reference statements)

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“…Ub signalling is antagonised by deubiquitinases (DUBs), which cleave the polyUb signal from substrates to terminate signalling [22]. OTU DUB with linear linkage specificity (OTULIN) and CYLD are the two main DUBs that regulate M1-polyUb signalling [23,24]. OTULIN exclusively cleaves M1 linkages [25,26], whereas CYLD cleaves both M1 and K63 linkages [27].…”

Section: Introductionmentioning

confidence: 99%

OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

et al. 2020

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Methionine-1 (M1)-linked polyubiquitin chains conjugated by the linear ubiquitin chain assembly complex (LUBAC) control NF-κB activation, immune homoeostasis, and prevents tumour necrosis factor (TNF)-induced cell death. The deubiquitinase OTULIN negatively regulates M1-linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. However, the cellular pathways and physiological functions controlled by OTULIN remain poorly understood. Here, we show that OTULIN prevents development of liver disease in mice and humans. In an ORAS patient, OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10–13 months of age. Similarly, liver-specific deletion of OTULIN in mice leads to neonatally onset steatosis and hepatitis, akin to the ORAS patient. OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver. In mice, steatosis progresses to steatohepatitis, fibrosis and pre-malignant tumour formation by 8 weeks of age, and by the age of 7–12 months the phenotype has advanced to malignant hepatocellular carcinoma. Surprisingly, the pathology in OTULIN-deficient livers is independent of TNFR1 signalling. Instead, we find that steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation, and inhibition of mTOR by rapamycin administration significantly reduces the liver pathology. Collectively, our results reveal that OTULIN is critical for maintaining liver homoeostasis and suggest that M1-linked polyubiquitin chains may play a role in regulation of mTOR signalling and metabolism in the liver.

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Section: Introductionmentioning

confidence: 99%

OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

et al. 2020

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“…With respect to alternative amino acids, evidence is rapidly emerging in animals that residues besides lysine can form adducts with Ub, including internal serines, threonines, and cysteines, and the N-terminal amino group (Komander and Rape, 2012; Kravtsova-Ivantsiv and Ciechanover, 2012; Elliott, 2016). Such non-canonical linkages have not yet been chemically confirmed in plants; in fact, designated searches of our MS datasets for these linkages failed to uncover any, suggesting that if they exist, they are likely rare in Arabidopsis .…”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Analyses Reveal a Central Role for Ubiquitylation in Remodeling the Arabidopsis Proteome during Photomorphogenesis

et al. 2017

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The switch from skotomorphogenesis to photomorphogenesis is a key developmental transition in the life of seed plants. While much of the underpinning proteome remodeling is driven by light-induced changes in gene expression, the proteolytic removal of specific proteins by the ubiquitin-26S proteasome system is also likely paramount. Through mass spectrometric analysis of ubiquitylated proteins affinity-purified from etiolated Arabidopsis seedlings before and after red-light irradiation, we identified a number of influential proteins whose ubiquitylation status is modified during this switch. We observed a substantial enrichment for proteins involved in auxin, abscisic acid, ethylene, and brassinosteroid signaling, peroxisome function, disease resistance, protein phosphorylation and light perception, including the phytochrome (Phy) A and phototropin photoreceptors. Soon after red-light treatment, PhyA becomes the dominant ubiquitylated species, with ubiquitin attachment sites mapped to six lysines. A PhyA mutant protected from ubiquitin addition at these sites is substantially more stable in planta upon photoconversion to Pfr and is hyperactive in driving photomorphogenesis. However, light still stimulates ubiquitylation and degradation of this mutant, implying that other attachment sites and/or proteolytic pathways exist. Collectively, we expand the catalog of ubiquitylation targets in Arabidopsis and show that this post-translational modification is central to the rewiring of plants for photoautotrophic growth.

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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 ubiquitination plays important roles in regulating immunity and cell death signaling cascades, as well as autophagy ( Fig. 3A-B) [30][31][32][33][34][35][36][37]. Thus far, the only E3 ligase complex known to generate linear ubiquitin chains is the "Linear Ubiquitin Chain Assembly Complex" (LUBAC), which consists of "Haeme-Oxidized IRP2 ubiquitin Ligase 1L" (HOIL-1L), "HOIL-1-Interacting Protein" (HOIP), and "Shank-Associated RH Domain-Interacting Protein" (SHARPIN) (Fig.…”

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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Molecular basis for specificity of the Met1-linked polyubiquitin signal

Cited by 21 publications

References 148 publications

OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer

Mass Spectrometric Analyses Reveal a Central Role for Ubiquitylation in Remodeling the Arabidopsis Proteome during Photomorphogenesis

Linear ubiquitin chain‐binding domains

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