Cellular functions and molecular mechanisms of non-lysine ubiquitination

McClellan, Amie J.; Laugesen, Sophie Heiden; Ellgaard, Lars

doi:10.1098/rsob.190147

Cited by 125 publications

(82 citation statements)

References 101 publications

(186 reference statements)

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“…Lysine/N-terminal amines, cysteine thiols or serine/threonine hydroxyls, attacks the electrophile thioester carbonyl of an E2–ubiquitin (Ub) conjugate. This results in a Ub–substrate conjugate linked by an isopeptide (lysine), peptide (N-terminal), thioester (cysteine) or hydroxyester bond (serine/threonine), respectively [ 41 ]. DDS, in particular, has nucleophilic sites for ubiquitination.…”

Section: Resultsmentioning

confidence: 99%

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4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

Lee

Sohn

et al. 2020

IJMS

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The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.

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Section: Resultsmentioning

confidence: 99%

“…DDS can compete with the ubiquitination cascade. Cysteine thiols and hydroxyls on serines, threonines, leucines, and tyrosines could also potentially be ubiquitinated by an identical mechanism [ 41 , 43 , 44 ].…”

Section: Figurementioning

confidence: 99%

4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

Lee

Sohn

et al. 2020

IJMS

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“…Almost all ubiquitin site profiling has focused on lysine modification. However, there are more and more examples of non-lysine ubiquitination in a variety of contexts [ 85 ] and there are few ubiquitomics methods for mapping these modifications. A few E3 ligases in humans have been discovered to possess esterification activity, ubiquitinating serine and threonine residues [ 86 , 87 ].…”

Section: Limitations Of Ubiquitin Site Profilingmentioning

confidence: 99%

Ubiquitomics: An Overview and Future

et al. 2020

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Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected to lysine, perhaps other amino acid side chains, and N-termini of proteins, often including branching of the ubiquitin chains. Understanding this enormous complexity in protein ubiquitination, the so-called ‘ubiquitin code’, in combination with the ∼1000 enzymes involved in controlling ubiquitin recognition, conjugation, and deconjugation, calls for novel developments in analytical techniques. Here, we review different headways in the field mainly driven by mass spectrometry and chemical biology, referred to as “ubiquitomics”, aiming to understand this system’s biological diversity.

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“…This process most commonly binds the last amino acid of ubiquitin (glycine 76) to an epsilon-amino group (ε-NH 3 + ) of lysine residue on the substrate (Mattiroli and Sixma, 2014). Recently, there is also increasing evidence of so-called non-canonical ubiquitination where non-lysine residues are ubiquitinated using non-amine groups, such as the sulfhydryl group on cysteine, and the hydroxyl group on threonine and serine (Kravtsova-Ivantsiv and Ciechanover, 2012;McClellan et al, 2019;McDowell and Philpott, 2013).…”

Section: Hbc and Ubiquitinationmentioning

confidence: 99%

Posttranslational modifications of HBV core protein

Lubyová¹,

Weber²

2020

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Infection with hepatitis B virus (HBV) often leads to development of chronic liver disease. In fact, 10% of infected adults and almost 90% of infected infants develop chronic hepatitis B associated with severe liver diseases, including acute liver failure, liver cirrhosis or hepatocellular carcinoma. At present there is no effective cure for chronic hepatitis B. The current treatment of chronically infected patients is long-term, expensive and relies on treatment with nucleos(t)ide analogs in combination with immune therapies, that frequently lead to adverse side effects. Recently, the National Institute of Health proposed strategic plan for Trans-NIH research to cure hepatitis B. The key priority is better understanding of HBV life cycle and its interactions with host cell. Due to the fact that HBV is a small double stranded DNA virus encoding only a limited number of proteins, HBV replication widely relies on host cell pathways and proteins. As demonstrated by numerous reports, HBV core protein (HBc) which is the main component of viral nucleocapsid, plays multiple roles in HBV life cycle and is engaged in many protein interaction networks of the host cell. Several recent studies have shown that HBV proteins can be modified by different types of posttranslational modifications (PTMs) that affect their protein-protein interactions, subcellular localization and function. In this review, we discuss diverse PTMs of HBc and their role in regulation of HBc function in the context of HBV replication and pathogenesis.

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Cellular functions and molecular mechanisms of non-lysine ubiquitination

Cited by 125 publications

References 101 publications

4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

Ubiquitomics: An Overview and Future

Posttranslational modifications of HBV core protein

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