Deubiquitinases: From mechanisms to their inhibition by small molecules

Molecular Cell, Journal Year: 2021, Volume and Issue: 82(1), P. 15 - 29

Published: Nov. 22, 2021

Language: Английский

---

A family of bacterial Josephin-like deubiquitinases with an irreversible cleavage mode

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

---

Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11971 - 11971

Published: Nov. 4, 2021

The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It widely known for its role degrading abnormal protein substrates maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) the proteasome. Therefore, aberrant expression these results an altered process, transduction signaling death survival, resulting cancer. In this review, overview of profuse as a pro-oncogenic or progressive growth factor tumors with their downstream pathways has been discussed. A systematic literature review PubMed, Medline, Bentham, Scopus, EMBASE (Elsevier) databases was carried out to understand nature extensive work done on modulation oncogenic signaling. Various vitro, vivo studies demonstrating involvement systems varied types cancers are also discussed current review. Several inhibitors E1, E3, deubiquitinase proteasome have applied treating Some drugs exhibited successful outcomes different cancer types, so clinical trials going inhibitors. This mainly focuses certain developing that can be targeted treat

Language: Английский

---

The Ubiquitination System within Bacterial Host–Pathogen Interactions

Microorganisms, Journal Year: 2021, Volume and Issue: 9(3), P. 638 - 638

Published: March 19, 2021

Ubiquitination of proteins, like phosphorylation and acetylation, is an important regulatory aspect influencing numerous various cell processes, such as immune response signaling autophagy. The study ubiquitination has become essential to learning about host–pathogen interactions, a better understanding the detailed mechanisms through which pathogens affect processes in host will contribute vaccine development effective treatment diseases. Pathogenic bacteria (e.g., Salmonella enterica, Legionella pneumophila Shigella flexneri) encode many effector deubiquitinating enzymes (DUBs), targeting ubiquitin machinery thus disrupting pertinent ubiquitin-dependent anti-bacterial response. We focus here upon system integral unit, its interconnection with regulation inflammation autophagy, primarily while examining manipulating system. Many bacterial proteins have already been described being translocated into cell, where they directly regulate defense processes. Due their importance pathogenic progression within host, are regarded virulence factors for evasion. However, some cases Francisella tularensis) influenced by infection, although responsible effectors still unknown.

Language: Английский

---

The Biochemistry of Cytoplasmic Incompatibility Caused by Endosymbiotic Bacteria

Genes, Journal Year: 2020, Volume and Issue: 11(8), P. 852 - 852

Published: July 25, 2020

Many species of arthropods carry maternally inherited bacterial endosymbionts that can influence host sexual reproduction to benefit the bacterium. The most well-known such reproductive parasites is Wolbachia pipientis. are obligate intracellular α-proteobacteria found in nearly half all arthropod species. This success has been attributed part their ability manipulate favor infected females. Cytoplasmic incompatibility (CI), a phenomenon wherein infection renders males sterile when they mate with uninfected females, but not females (the rescue mating), appears be common. CI provides advantage presence threshold level males. molecular mechanisms and other manipulations, as male killing, parthenogenesis, feminization, have remained mysterious for many decades. It had proposed by Werren more than two decades ago caused Wolbachia-mediated sperm modification achieved Wolbachia-encoded factor egg. In past few years, new research highlighted set syntenic gene pairs encoding CI-inducing factors (Cifs) key players induction its rescue. Within each Cif pair, protein encoded upstream denoted A downstream B. To date, types Cifs characterized based on enzymatic activity identified B pair; one type encodes deubiquitylase (thus named or cid), second nuclease (named cin). CidA CinA proteins bind tightly specifically respective CidB CinB partners. transgenic Drosophila melanogaster, expression either Cid Cin pair germline induces cognate sufficient With identity now known, field turned directed studies CI, which we review here.

Language: Английский

---

High-throughput matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry–based deubiquitylating enzyme assay for drug discovery

Nature Protocols, Journal Year: 2020, Volume and Issue: 15(12), P. 4034 - 4057

Published: Nov. 2, 2020

Language: Английский

---

Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Nov. 13, 2020

Legionella pneumophila causes a severe pneumonia known as Legionnaires' disease. During the infection, injects more than 300 effector proteins into host cells. Among them are enzymes involved in altering host-ubiquitination system. Here, we identified two LegionellaOTU (ovarian tumor)-like deubiquitinases (LOT-DUBs; LotB [Lpg1621/Ceg23] and LotC [Lpg2529]). The crystal structure of catalytic core (LotC14-310) was determined at 2.4 Å. Unlike classical OTU-family, LOT-family shows an extended helical lobe between Cys-loop variable loop, which defines unique class OTU-DUBs. has additional ubiquitin-binding site (S1'), enables specific cleavage Lys63-linked polyubiquitin chains. By contrast, only contains S1 cleaves different species ubiquitin MS analysis categories host-interacting substrates. Together, our results provide new structural insights bacterial OTU-DUBs indicate distinct roles host-pathogen interactions.

Language: Английский

---

The ubiquitin ligation machinery in the defense against bacterial pathogens

EMBO Reports, Journal Year: 2021, Volume and Issue: 22(11)

Published: Sept. 13, 2021

Review13 September 2021Open Access The ubiquitin ligation machinery in the defense against bacterial pathogens Ishita Tripathi-Giesgen Department of Molecular Machines and Signaling, Max Planck Institute Biochemistry, Martinsried, Germany Search for more papers by this author Christian Behrends Corresponding Author [email protected] orcid.org/0000-0002-9184-7607 Munich Cluster Systems Neurology (SyNergy), Medical Faculty, Ludwig-Maximilians-University München, Arno F Alpi orcid.org/0000-0002-9572-7266 Information Tripathi-Giesgen1, *,2 *,1 1Department 2Munich *Corresponding author. Tel: +49(0)89440046509; E-mail: +49(0)8985782480; EMBO Reports (2021)22:e52864https://doi.org/10.15252/embr.202152864 See Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract system is an important part host cellular program during infection. This particular evident a number bacteria including Salmonella Typhimurium Mycobacterium tuberculosis which—inventively as their invasion strategy or accidentally upon rupture seized endomembranes—become exposed cytosol. Ubiquitylation involved detection clearance these well activation innate immune inflammatory signaling. Remarkably, all responses seem emanate from dense layer which coats invading pathogens. In review, we focus on diverse group cell E3 ligases that help tailor coat. particular, address how divergent conjugation mechanisms contribute complexity anti-bacterial coating recruitment different ubiquitin-binding effectors. We also discuss coordination strategies evolved evade activities system. ARIH1 ARIadne 1 homolog ATG Autophagy-related BMDM Bone marrow-derived macrophages BMP morphogenic protein CALCOCO Calcium-binding coiled-coil domain-containing CC1 Coiled-coil CRL Cullin RING ligase DUB Deubiquitinating enzyme GAS Group A streptococcus GIR Galectin interacting region GWAS Genomewide association study HECT Homologous E6AP carboxyl terminus HHAR1 Homologues human HOIL-IL Heme-oxidized IRP2 Ub 1L HOIP HOIL-1-interacting IBR between IKK IκB kinase LAP LC3-associated phagocytosis LDD Linear Ub-determining domain LIR LC3-interacting LPS Lipopolysaccharide LRR leucine-rich repeat LRSAM1 Leucine-rich sterile alpha motif-containing LUBAC assembly complex MAP1LC3B Microtubule-associated proteins 1A/1B light-chain 3B NBR1 Neighbor BRCA1 NDP52 Nuclear dot 52 NEL Novel NEMO NF-kB essential modifier factor kappa-B NOD1 Nucleotide-binding oligomerization OMP Outer membrane OPTN Optineurin OTULIN OTU with LINear linkage specificity PAMP Pathogen-associated molecular pattern PE Phosphatidylethanolamine PINK1 PTEN-induced RBR RING-between-RING Really interesting new gene RNF213 Ring finger 213 SAM Sterile SCV Salmonella-containing vacuole SHARPIN Shank-associated RH SIM Structured illumination microscopy SLO Streptolysin O Smurf1 SMAD regulator SQSTM1 Sequestosome-1 TAK1 Transforming growth factor-β-activated TBK1 TANK-binding TGF-β transforming beta TLR Toll-like receptor TRAF2 TNF receptor-associated 2 TRIM21 Tripartite 21 TXN Thioredoxin Ubiquitin UBA Ubiquitin-associated UBL Ubiquitin-like UPD Unique Parkin UVRAG UV radiation resistance associated ZF Zinc Introduction Most mammalian types have capacity defend protect themselves pathogens, thereby contributing cell-autonomous immunity. Over last two decades, macroautophagy has emerged critical immunity pathway detects variety cytosolic initiates disposal. Originally, been described catabolic process sequesters unwanted intracellular components, misfolded dysfunctional organelles, eliminates them through lysosomal degradation (Fig. 1A). hallmark de novo formation double-membrane vesicle called autophagosome (Nakatogawa, 2020). Autophagosome biogenesis proceeds isolated crescent-shaped structure (called phagophore isolation membrane) derived preexisting endomembranes ER grows around, ultimately encloses components. To complete macroautophagy, fuses lysosome, forming autolysosome allow disintegration inner sequestered material hydrolases, such lipases, proteases, glycosylases, nucleases (Glick et al, 2010; Rubinsztein 2012). date, increasing autophagy-related (ATG) identified are its fusion lysosome. Their details mechanistic interactions worked out over description, however, would exceed scope review interested reader referred some excellent recent reviews (Noda Inagaki, 2015; Nakatogawa, Figure 1. Selective (A) Key steps selective macroautophagy. (1) initiated membranes vesicles gradually expand mature phagophores decorated membrane-anchored LC3 GABARAPs (orange hexagons). (2) These act binding site autophagy cargo receptors (brown) allowing direct delivery accumulation cargo. Finally, closes double-membraned (3), subsequently lysosome (4), where content degraded enzymes. (B) Xenophagy, Salmonella. enters cells (SCV) protects it surveillance serves replicative niche. SCVs can access proteins. (3) glycans, normally present outer side membrane, serve danger signals recognized galectins (purple triangles). Besides, detected generate coat, consistent linkage-type chains (red orange circles), around (4) Both, recruit mediate capture LC3-conjugated autophagosomes (5) targeted (6). Download figure PowerPoint Macroautophagy comes flavors, depending targets sequestered. During bulk engulfs randomly cytoplasmic components close by. form active at basal level nutrient-rich conditions, but be upregulated response several stress starvation, playing integral recycling nutrients maintaining energy homeostasis. By contrast, certain molecules, structures, organelles via eat-me target-specific named receptors, turn stepwise initiate scaffold exclusively distinct (Reggiori 2012; Stolz 2014; Zaffagnini Martens, 2016). classified according cargo, mitophagy (mitochondria), ribophagy (ribosomes), ER-phagy (ER), lipophagy (lipid droplets), lysophagy (lysosomes), pexophagy (peroxisomes) (Gatica 2018). However, utilize not only clear recycle own material, eliminate invaded commonly known antimicrobial xenophagy—from Greek 'foreign/strange' 'eating' (Hu Non-canonical forms do involve (LAP) (Sanjuan 2007; Mehta Heckmann 2017; Martinez, will our current understanding xenophagy advances role (Ub) targeting pathogenic developed ways fend off survival even hijack benefit. Mechanism ubiquitin-mediated Intracellular Shigella flexneri (S. flexneri), (M. tuberculosis), enterica serovar Typhimurium), Listeria monocytogenes (L. monocytogenes), able reside reproduce inside responsible many severe diseases. Besides passive engulfment neutrophils phagocytosis, actively invade endothelial epithelial (Cossart Sansonetti, 2004). Following entry, either membranous compartments (vacuoles) escape Nevertheless, target restrict replication. Since S. one best-studied examples eliminated (Herhaus Dikic, 2018), use model substrate describe key features 1B). After internalization, resides acidic compartment (SCV). permissive niche (LaRock 2015). Numerous genes, effector SifA, required extension surface accommodate replicating bacteria. early phase infection (usually within first hour), subset damaged specific signature molecules become wall luminal SCV. Specifically, β-galactosides—which modify extracellular plasma endosomes—are fast β-galactoside-binding lectin, galectin-8 acts damage and/or pattern-recognition directly associates (also CALCOCO2) galectin-interacting (GIR) motif (Thurston β-galactosides/galectin-8-initiated autophagy, activate trigger coat dressing whole (Perrin Ubiquitylation, covalent attachment proteins, requires orchestrated action least three enzymes working relay, Ub-activating (E1), Ub-conjugating (E2), (E3) (Hershko 2000; Buetow Huang, E3s play central into families presence characteristic domains mechanism transfer usually lysine residues proteins: really (RING) catalyze allosteric E2˜Ub conjugate (˜ indicating thioester bond) E2 substrate, whereas homologous (HECT) Ring-Between-Ring (RBR) catalytic cysteine transient E3˜Ub before mediating onto substrates (Zheng Shabek, 2017). Substrates modified single multiple lysins (mono- multi-monoubiquitylation) polyubiquitin (polyubiquitylation) formed linking seven (K6, K11, K27, K29, K33, K48, K63) N-terminal methionine (M1). structurally come variations, homotypic (single type) heterotypic (multiple, mixed types) branched chains, resulting code (Komander Rape, Identity origin ubiquitylation were assessed quantitative proteomics Typhimurium-infected revealed sites membrane-associated (Fiskin Moreover, chain M1- linear chains), K48-, K63-polyubiquitin linkages, suggesting signaling platform (van Wijk Manzanillo 2013). like Smurf1, Parkin, ARIH1, LRSAM1, RNF213, LUBAC, ubiquitylate than type bacteria, cases, simultaneously ligases. For instance, colocalize promote formation. There RNF166 (Heath 2016), MARCH8 (Jin 2017), (Hos 2020), TRIM22 (Lou TRIM16 (Chauhan 2016) recognize pathogen itself other aspects glycans Similar Galectin-8, functions xenophagic signal (Birmingham 2006) triggers p62 (alias SQSTM1), CALCOCO2), optineurin (OPTN) 2009; Wild 2011; Thurston multifunctional harboring (UBD) inherent specificities toward types, protein–protein interaction motifs induce elongation proximal (Kirkin Rogov, 2019). modular nature best understood case employs Ub-binding zinc (ZF) associate SKICH promoting ULK1 kinases respective adaptors FIP200 SINBAD/NAP1 (LIR) guide nascent LC3C (von Muhlinen Ravenhill While NDP52's seems promiscuously bind mono- (Xie 2015), UBAN specifically recognizes K63-linked (Wild 2011). TBK1-mediated phosphorylation fosters LC3, supporting phagosome/autophagosome restriction Notably, actions limited xenophagy, shared among processes aggrephagy (Turco 2019; Vargas Shi 2020; Yamano special tuberculosis, M. Rv1468c leading LC3-mediated lysosomes (Chai Hence, plays sensor highlighting importance xenophagy. nonmotile ΔactA mutant L. was Perrin colleagues 2004 seminal discovery extensive research efforts past decades identify Ub-targeting cytosol Ub-mediated responses. chapter, historic order identification xenophagy-associated knowledge E3-typical context (i) sensing/recognition (ii) (iii) modification. 2011, ligase, (LRSAM1), functionally linked synthesis (Ng shown endosomal sorting (Amit 2004; McDonald Martin-Serrano, 2008), belongs RING-type share 2). Canonical comprise conserved cysteines histidines coordinate ions stabilizing overall globular three-dimensional (Deshaies Joazeiro, 2009). lack activity, charged architecture closed conformation allosterically activates nucleophilic attack suitable placed isopeptide bond (Dou 2012, 2013; Plechanovova Pruneda Branigan Apart C-terminal domain, contains (LRR) N terminus, (SAM domain), (CC1 CC2), regulate activity self-associated oligomers (Bian 2. showing repeats dotted box) PAMPs mediates binding, (CC) domains, (SAM) containing C activity. LRSAM1-mediated Salmonella, preferentially K6- K27-linked leads machinery. LRRs typically pathogen-associated patterns (PAMPs) making suitably designed recognizing ubiquitylating LRR-mediated recognition already proposed time when observed colocalizes xenophagy-susceptible Typhimurium, EGD-e, flexneri, invasive Escherichia coli, colocalization mediated (Huett characterized yet dispensable association; bacteria-associated preference vitro. Whether bacteria-bound autoubiquitylated entirely clear. peaking 40 min post-infection coinciding galectin-8/NDP52 colocalization. mark spatially subdomains recruited independently follows occurring hour thought foster necessary functional control Depletion promotes Typhimurium. Lymphoblasts Charcot–Marie–Tooth disease patients, expression due frameshift truncates entire less efficient controlling replication virulent strain (i.e. NTCC12023; 2012)). Conversely, bactericide Biochanin A, plant isoflavone derivate, enhance killing infected HeLa reinforced LRSAM1/NDP52 (Zhao underlying A's bactericidal known, though. E3, may step establishment initial Typhimurium; became further re-modeled create PARKIN studies (GWAS) genetic polymorphism parkin (PRKN) increased susceptibility leprae, potential connection mitochondrial homeostasis (Mira Ali 2006). primarily well-established got much attention frequently mutated autosomal recessive juvenile Parkinsonism, neurological disorder progressive loss dopaminergic neurons. family defined common organization (reviewed (Cotton Lechtenberg, 2020)). module consists zinc-binding motifs: RING1 canonical fold followed In-Between-RING (IBR) finally Rcat RING2) 3A). Specific Ub-like (UBL) shares structural similar additional zinc-coordinating unique (UPD) RING0) (Trempe regulating Parkin's apo-form adopts multilayered autoinhibited conformation, whereby repressor element (REP) occlude RING1, masks 431 (C431) preventing intermediate (Chaugule Trempe Wauer Komander, Several elegant striking mitophagy. depends kinase, accumulates activated mitochondria (Matsuda Narendra Vives-Bauza Kondapalli phosphorylates serine 65 (pS65-Ub) increases Ub's affinity site—a pS65-Ub-binding pocket—in Parkin. Once bound, pS65-Ub induces conformational change release inhibitory module, destabilizing autoinhibitory accessible transthiolation. Subsequently, freed becomes pS65-UBL open, (Ordureau Kazlauskaite Kumar Sauve Aguirre Gladkova 3. RBR-type Diagram (UPD), (REP), regulatory comprising terminus. remains addressed infection, decorates (predominantly K63 chains) recruits triggering Domain subunits LUBAC: HOIP, HOIL-IL, SHARPIN. interact (solid lines), contribution double NZF (dNZF) (dotted line). dNZF boxes) two-phase mechanism: phase, binds second enhanced M1-linked binding. M1-Ub adapter pro-inflammatory response, respectively. CYLD counterbalance (C) Schematic view acidic/glycine region, UBA-like (UBAL), Ariadne K48-Ub chains. activation, downstream ARIH1-mediated understood. PINK1/Parkin tightly mitochondria, rather surprising, vacuolar phagosomal after entering cell. Due mycobacterial ESX-1 secretion system, permeable Ub-xenophagy (Watson murine bone (BMDMs), predominantly surrounding phagosomes. contrasts findings Ordureau al (2014) does exhibit (Manzanillo 2014). Parkin-mediated UBZ respectively, facilitate mycobacteria (Ichimura 2008; Watson vivo data support range infections. Park2−/− mice extreme D. melanogaster C. elegans strains deficient Parc2 homologues highly susceptible monocytogenes, marinum, conserv

Language: Английский

---

Deubiquitinases in Neurodegeneration

Cells, Journal Year: 2022, Volume and Issue: 11(3), P. 556 - 556

Published: Feb. 5, 2022

Ubiquitination refers to the conjugation of ubiquitin protein (a small highly conserved among eukaryotes) itself or other proteins through differential use ubiquitin's seven internal linkage sites amino-terminal amino group. By creating different chain lengths, an enormous proteomic diversity may be formed. This creates a signaling system that is central controlling almost every conceivable function, from proteostasis regulating enzyme function and everything in between. Protein ubiquitination reversed activity deubiquitinases (DUBs), enzymes deconjugate substrates. DUBs are regulated several mechanisms, controlled subcellular localization within cells developmental tissue specific expression. Misregulation has been implicated diseases including cancer neurodegeneration. Here we present brief overview role neurodegeneration, as potential therapeutic targets.

Language: Английский

---

The Role of Deubiquitinases in Virus Replication and Host Innate Immune Response

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 24, 2022

As a critical post-translational modification, ubiquitination is known to affect almost all the cellular processes including immunity, signaling pathways, cell death, cancer development, and viral infection by controlling protein stability. Deubiquitinases (DUBs) cleave ubiquitin from proteins reverse process of ubiquitination. Thus, DUBs play an important role in deubiquitination serve as therapeutic targets for various diseases. are found eukaryotes, bacteria, viruses influence biological processes. Here, we summarize recent findings on function modulating infection, mechanism which regulate host innate immune response, highlight those that have recently been discovered antiviral targets.

Language: Английский

---