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Characterization and development of SAPP as a specific peptidic inhibitor that targets Porphyromonas gingivalis.
Ho MH, Lamont RJ, Chazin WJ, Chen H, Young DF, Kumar P, Xie H
(2018) Mol Oral Microbiol 33: 430-439
MeSH Terms: Adhesins, Bacterial, Bacterial Adhesion, Biofilms, Cell Membrane, Cysteine Endopeptidases, Dental Plaque, Fibroblasts, Humans, Peptides, Periodontitis, Porphyromonas gingivalis, Virulence
Show Abstract · Added March 26, 2019
Porphyromonas gingivalis is a keystone bacterium in the oral microbial communities that elicits a dysbiosis between the microbiota and the host. Therefore, inhibition of this organism in dental plaques has been one of the strategies for preventing and treating chronic periodontitis. We previously identified a Streptococcal ArcA derived Anti-P gingivalils Peptide (SAPP) that in vitro, is capable of repressing the expression of several virulence genes in the organism. This leads to a significant reduction in P gingivalis virulence potential, including its ability to colonize on the surface of Streptococcus gordonii, to invade human oral epithelial cells, and to produce gingipains. In this study, we showed that SAPP had minimal cytotoxicity to human oral keratinocytes and gingival fibroblasts. We observed that SAPP directly bound to the cell surface of P gingivalis, and that alterations in the sequence at the N-terminus of SAPP diminished its abilities to interact with P gingivalis cells and repressed the expression of virulence genes. Most strikingly, we demonstrated using an ex-vivo assay that besides its inhibitory activity against P gingivalis colonization, SAPP could also reduce the levels of several other oral Gram-negative bacteria strongly associated with periodontitis in multispecies biofilms. Our results provide a platform for the development of SAPP-targeted therapeutics against chronic periodontitis.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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MeSH Terms
A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo.
Brezski RJ, Kinder M, Grugan KD, Soring KL, Carton J, Greenplate AR, Petley T, Capaldi D, Brosnan K, Emmell E, Watson S, Jordan RE
(2014) MAbs 6: 1265-73
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Antibody-Dependent Cell Cytotoxicity, Bacterial Proteins, Blood Platelets, Cell Line, Cell Line, Tumor, Cysteine Endopeptidases, Dogs, Enzyme-Linked Immunosorbent Assay, Epitopes, Humans, Immunoglobulin Fab Fragments, Immunoglobulin G, Matrix Metalloproteinase 3, Platelet Count, Proteolysis, Rats, Rituximab
Show Abstract · Added April 22, 2016
We report a chimeric monoclonal antibody (mAb) directed to a neo-epitope that is exposed in the IgG lower hinge following proteolytic cleavage. The mAb, designated 2095-2, displays specificity for IdeS-generated F(ab')₂ fragments, but not for full-length IgG or for closely-related F(ab')₂ fragments generated with other proteases. A critical component of the specificity is provided by the C-terminal amino acid of the epitope corresponding to gly-236 in the IgG1 (also IgG4) hinge. By its ability to bind to IdeS-cleaved anti-CD20 mAb, mAb 2095-2 fully restored antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against WIL2-S cells to the otherwise inactive anti-CD20 IgG1 F(ab')₂ fragment. Similarly, 2095-2 reinstated ADCC against MDA-MB-231 cells to an anti-CD142 IgG1 F(ab')₂ fragment. mAb 2095-2 was also capable of eliciting both CDC and ADCC to IgG4 F(ab')₂ fragments, an IgG subclass that has weaker ADCC and CDC when intact relative to intact IgG1. The in vitro cell-based efficacy of 2095-2 was extended to the in vivo setting using platelets as a cell clearance surrogate. In a canine model, the co-administration of 2095-2 together with IdeS-generated, platelet-targeting anti-CD41/61 F(ab')₂ fragment not only restored platelet clearance, but did so at a rate and extent of clearance that exceeded that of intact anti-CD41/61 IgG at comparable concentrations. To further explore this unexpected amplification effect, we conducted a rat study in which 2095-2 was administered at a series of doses in combination with a fixed dose of anti-CD41/61 F(ab')₂ fragments. Again, the combination, at ratios as low as 1:10 (w/w) 2095-2 to F(ab')₂, proved more effective than the anti-CD41/61 IgG1 alone. These findings suggest a novel mechanism for enhancing antibody-mediated cell-killing effector functions with potential applications in pathologic settings such as tumors and acute infections where protease activity is abundant.
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20 MeSH Terms
Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.
Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, Wongsiriroj N, Nagy HM, Ivanova PT, Scott SA, Knittelfelder O, Rechberger GN, Birner-Gruenberger R, Eder S, Brown HA, Haemmerle G, Oberer M, Lass A, Kershaw EE, Zimmermann R, Zechner R
(2012) Cell Metab 15: 691-702
MeSH Terms: 1-Acylglycerol-3-Phosphate O-Acyltransferase, Acyl Coenzyme A, Acyltransferases, Animals, CHO Cells, COS Cells, Cercopithecus aethiops, Cricetinae, Cysteine Endopeptidases, Dietary Sucrose, Fatty Liver, Hep G2 Cells, Humans, Lipid Metabolism, Lipids, Liver, Lysophospholipids, Male, Membrane Proteins, Mice, Mice, Knockout, Models, Molecular, Phosphatidic Acids, Phospholipids, Polymorphism, Genetic, Triglycerides, Up-Regulation
Show Abstract · Added March 21, 2013
Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
Copyright © 2012 Elsevier Inc. All rights reserved.
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27 MeSH Terms
Imaging protein complex formation in the autophagy pathway: analysis of the interaction of LC3 and Atg4B(C74A) in live cells using Förster resonance energy transfer and fluorescence recovery after photobleaching.
Kraft LJ, Kenworthy AK
(2012) J Biomed Opt 17: 011008
MeSH Terms: Animals, COS Cells, Cell Nucleus, Cercopithecus aethiops, Cysteine Endopeptidases, Cytoplasm, Fluorescence Recovery After Photobleaching, Fluorescence Resonance Energy Transfer, Green Fluorescent Proteins, Microscopy, Fluorescence, Microtubule-Associated Proteins, Models, Biological, Multiprotein Complexes, Single-Cell Analysis
Show Abstract · Added December 10, 2013
The protein microtubule-associated protein 1, light chain 3 (LC3) functions in autophagosome formation and plays a central role in the autophagy pathway. Previously, we found LC3 diffuses more slowly in cells than is expected for a freely diffusing monomer, suggesting it may constitutively associate with a macromolecular complex containing other protein components of the pathway. In the current study, we used Förster resonance energy transfer (FRET) microscopy and fluorescence recovery after photobleaching (FRAP) to investigate the interactions of LC3 with Atg4B(C74A), a catalytically inactive mutant of the cysteine protease involved in lipidation and de-lipidation of LC3, as a model system to probe protein complex formation in the autophagy pathway. We show Atg4B(C74A) is in FRET proximity with LC3 in both the cytoplasm and nucleus of living cells, consistent with previous biochemical evidence that suggests these proteins directly interact. In addition, overexpressed Atg4B(C74A) diffuses significantly more slowly than predicted based on its molecular weight, and its translational diffusion coefficient is significantly slowed upon coexpression with LC3 to match that of LC3 itself. Taken together, these results suggest Atg4B(C74A) and LC3 are contained within the same multiprotein complex and that this complex exists in both the cytoplasm and nucleoplasm of living cells.
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14 MeSH Terms
Temperature-sensitive mutants and revertants in the coronavirus nonstructural protein 5 protease (3CLpro) define residues involved in long-distance communication and regulation of protease activity.
Stobart CC, Lee AS, Lu X, Denison MR
(2012) J Virol 86: 4801-10
MeSH Terms: Alleles, Amino Acid Sequence, Amino Acid Substitution, Animals, Cricetinae, Cysteine Endopeptidases, Enzyme Activation, Gene Order, Mice, Models, Molecular, Molecular Sequence Data, Murine hepatitis virus, Mutation, Phenotype, Protein Structure, Tertiary, Sequence Alignment, Temperature, Virus Replication
Show Abstract · Added February 19, 2015
Positive-strand RNA virus genomes are translated into polyproteins that are processed by viral proteases to yield functional intermediate and mature proteins. Coronaviruses (CoVs) carry genes that encode an nsp5 protease (also known as 3CLpro or Mpro) responsible for 11 maturation cleavages. The nsp5 structure contains two chymotrypsin-like domains (D1 and D2) and a unique domain (D3), and forms functional dimers. However, little is known of interactions or communication across the structure of the protease during nsp5 activity. Using reverse genetic mutagenesis of the CoV murine hepatitis virus (MHV) nsp5, we identified a new temperature-sensitive (ts) mutation in D2 of nsp5 (Ser133Ala) and confirmed a ts residue in D3 (Phe219Leu). Both D2-tsS133A and D3-tsF219L were impaired for viral replication and nsp5-mediated polyprotein processing at the nonpermissive temperature. Passage of tsS133A and tsF219L at the nonpermissive temperature resulted in emergence of multiple second-site suppressor mutations, singly and in combinations. Among the second-site mutations, a D2 His134Tyr change suppressed the ts phenotype of D2-tsS133A and D3-tsF219L, as well as the previously reported D2-tsV148A. Analysis of multiple CoV nsp5 structures, and alignment of nonredundant nsp5 primary sequences, demonstrated that ts and suppressor residues are not conserved across CoVs and are physically distant (>10 Å) from each other, from catalytic and substrate-binding residues, and from the nsp5 dimer interface. These findings demonstrate that long-distance communication pathways between multiple residues and domains of nsp5 play a significant role in nsp5 activity and viral replication, suggesting possible novel targets for non-active site inhibitors of nsp5.
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18 MeSH Terms
Letter to the editor. Chemical-genetic strategy for inhibiting proteasome function in Saccharomyces cerevisiae.
Howard GC, Collins GA, Tansey WP
(2012) Yeast 29: 93-4
MeSH Terms: ATP-Binding Cassette Transporters, Cysteine Endopeptidases, DNA, Mitochondrial, Gene Deletion, Genome, Fungal, Leupeptins, Proline, Proteasome Endopeptidase Complex, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sodium Dodecyl Sulfate, Species Specificity
Added March 10, 2014
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12 MeSH Terms
Inhibition of thrombin formation by active site mutated (S360A) activated protein C.
Nicolaes GA, Bock PE, Segers K, Wildhagen KC, Dahlbäck B, Rosing J
(2010) J Biol Chem 285: 22890-900
MeSH Terms: Arginine, Binding, Competitive, Blood Coagulation, Blood Coagulation Factors, Catalytic Domain, Cell Line, Cysteine Endopeptidases, Enzyme Activation, Humans, Models, Molecular, Mutation, Neoplasm Proteins, Protein C, Protein S, Protein Stability, Recombinant Proteins, Thrombin
Show Abstract · Added January 20, 2015
Activated protein C (APC) down-regulates thrombin formation through proteolytic inactivation of factor Va (FVa) by cleavage at Arg(506) and Arg(306) and of factor VIIIa (FVIIIa) by cleavage at Arg(336) and Arg(562). To study substrate recognition by APC, active site-mutated APC (APC(S360A)) was used, which lacks proteolytic activity but exhibits anticoagulant activity. Experiments in model systems and in plasma show that APC(S360A), and not its zymogen protein C(S360A), expresses anticoagulant activities by competing with activated coagulation factors X and IX for binding to FVa and FVIIIa, respectively. APC(S360A) bound to FVa with a K(D) of 0.11 +/- 0.05 nm and competed with active site-labeled Oregon Green activated coagulation factor X for binding to FVa. The binding of APC(S360A) to FVa was not affected by protein S but was inhibited by prothrombin. APC(S360A) binding to FVa was critically dependent upon the presence of Arg(506) and not Arg(306) and additionally required an active site accessible to substrates. Inhibition of FVIIIa activity by APC(S360A) was >100-fold less efficient than inhibition of FVa. Our results show that despite exosite interactions near the Arg(506) cleavage site, binding of APC(S360A) to FVa is almost completely dependent on Arg(506) interacting with APC(S360A) to form a nonproductive Michaelis complex. Because docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactors, we hypothesize that the observed anticoagulant activity may be important for in vivo regulation of thrombin formation.
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17 MeSH Terms
Natural killer T cell-a cat o' nine lives!
Joyce S, Gordy LE
(2010) EMBO J 29: 1475-6
MeSH Terms: Animals, Apoptosis, Cysteine Endopeptidases, Lymphopoiesis, Mice, Mice, Knockout, NF-kappa B, Natural Killer T-Cells, Receptors, Interleukin-7
Added May 19, 2014
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9 MeSH Terms
Evidence for a role of immunoproteasomes in regulating cardiac muscle mass in diabetic mice.
Zu L, Bedja D, Fox-Talbot K, Gabrielson KL, Van Kaer L, Becker LC, Cai ZP
(2010) J Mol Cell Cardiol 49: 5-15
MeSH Terms: Animals, Cysteine Endopeptidases, Diabetes Mellitus, Glucose, Heart, Hyperglycemia, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardium, Myosin Heavy Chains, PTEN Phosphohydrolase, Proteasome Endopeptidase Complex, Streptozocin, Ubiquitin
Show Abstract · Added December 10, 2013
The ubiquitin-proteasome system plays an important role in regulating muscle mass. Inducible immunoproteasome subunits LMP-2 and LMP-7 are constitutively expressed in the heart; however, their regulation and functions are poorly understood. We here investigated the hypothesis that immunoproteasomes regulate cardiac muscle mass in diabetic mice. Type 1 diabetes was induced in wildtype mice by streptozotocin. After hyperglycemia developed, insulin and the proteasome inhibitor epoxomicin were used to treat diabetic mice for 6weeks. Isolated mouse hearts were perfused with control or high glucose solution. Catalytic proteasome beta-subunits and proteolytic activities were analyzed in the heart by immunoblotting and fluorogenic peptide degradation assays, respectively. Insulin and epoxomicin blocked loss of heart weight and improved cardiac function in diabetic mice. LMP-7 and its corresponding chymotryptic-like proteasome activity were increased in diabetic hearts and high glucose-treated hearts. Myosin heavy chain protein was decreased in diabetic hearts, which was largely reversed by epoxomicin. High glucose decreased LMP-2 protein levels in perfused hearts. In diabetic hearts, LMP-2 expression was downregulated whereas expression of the phosphatase and tensin homologue deleted on chromosome ten (PTEN) and the muscle atrophy F-box were upregulated. Moreover, mice with muscle-specific knockout of PTEN gene demonstrated increased cardiac muscle mass, while mice with LMP-2 deficiency demonstrated PTEN accumulation, muscle mass loss, and contractile impairment in the heart. Therefore, we concluded that high glucose regulates immunoproteasome subunits and modifies proteasome activities in the heart, and that dysregulated immunoproteasome subunits may mediate loss of cardiac muscle mass in experimental diabetic mice.
Copyright 2010 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Genetic and pharmacologic alteration of cathepsin expression influences reovirus pathogenesis.
Johnson EM, Doyle JD, Wetzel JD, McClung RP, Katunuma N, Chappell JD, Washington MK, Dermody TS
(2009) J Virol 83: 9630-40
MeSH Terms: Animals, Brain, Cathepsin B, Cathepsin L, Cathepsins, Cell Line, Cysteine Endopeptidases, Gene Expression Regulation, Inflammation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Reoviridae, Reoviridae Infections, Time Factors
Show Abstract · Added December 10, 2013
The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt), Ctsb(-/-), Ctsl(-/-), and Ctss(-/-) mice with the virulent reovirus strain T3SA+. The survival rate of Ctsb(-/-) mice was enhanced in comparison to that of wt mice, whereas the survival rates of Ctsl(-/-) and Ctss(-/-) mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in Ctsl(-/-) and Ctss(-/-) mice in comparison to the levels for wt and Ctsb(-/-) mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively, these data indicate that cathepsins B, L, and S influence reovirus pathogenesis and suggest that pharmacologic modulation of cathepsin activity diminishes reovirus disease severity.
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16 MeSH Terms