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  1 / 1002 MEDLINE  
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PMID:28449241
Autor:Knuppertz L; Osiewacz HD
Endereço:Institute of Molecular Biosciences and Cluster of Excellence 'Macromolecular Complexes', Department of Biosciences, J. W. Goethe University, Frankfurt, Germany.
Título:Autophagy compensates impaired energy metabolism in CLPXP-deficient Podospora anserina strains and extends healthspan.
Fonte:Aging Cell; 16(4):704-715, 2017 Aug.
ISSN:1474-9726
País de publicação:England
Idioma:eng
Resumo:The degradation of nonfunctional mitochondrial proteins is of fundamental relevance for maintenance of cellular homeostasis. The heteromeric CLPXP protein complex in the mitochondrial matrix is part of this process. In the fungal aging model Podospora anserina, ablation of CLPXP leads to an increase in healthy lifespan. Here, we report that this counterintuitive increase depends on a functional autophagy machinery. In PaClpXP mutants, autophagy is involved in energy conservation and the compensation of impairments in respiration. Strikingly, despite the impact on mitochondrial function, it is not mitophagy but general autophagy that is constitutively induced and required for longevity. In contrast, in another long-lived mutant ablated for the mitochondrial PaIAP protease, autophagy is neither induced nor required for lifespan extension. Our data provide novel mechanistic insights into the capacity of different forms of autophagy to compensate impairments of specific components of the complex mitochondrial quality control network and about the biological role of mitochondrial CLPXP in the control of cellular energy metabolism.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Fungal Proteins); EC 3.4.21.92 (Endopeptidase Clp)


  2 / 1002 MEDLINE  
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PMID:28937985
Autor:Llamas E; Pulido P; Rodriguez-Concepcion M
Endereço:Centre for Research in Agricultural Genomics (CRAG) CSIC-IRTA-UAB-UB, Campus UAB Bellaterra, Barcelona, Spain.
Título:Interference with plastome gene expression and Clp protease activity in Arabidopsis triggers a chloroplast unfolded protein response to restore protein homeostasis.
Fonte:PLoS Genet; 13(9):e1007022, 2017 Sep.
ISSN:1553-7404
País de publicação:United States
Idioma:eng
Resumo:Disruption of protein homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme. The repair pathway is promoted when the levels of ClpB3 proteins increase upon reduction of Clp protease activity in mutants or wild-type plants treated with the chloroplast protein synthesis inhibitor lincomycin (LIN). Here we show that LIN treatment rapidly increases the levels of aggregated proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones. As a consequence, folding capacity is increased to restore protein homeostasis. This sort of chloroplast unfolded protein response (cpUPR) mechanism appears to be mediated by the heat shock transcription factor HsfA2. Expression of HsfA2 and cpUPR-related target genes is independent of GUN1, a central integrator of retrograde signaling pathways. However, double mutants defective in both GUN1 and plastome gene expression (or Clp protease activity) are seedling lethal, confirming that the GUN1 protein is essential for protein homeostasis in chloroplasts.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (APG6 protein, Arabidopsis); 0 (Arabidopsis Proteins); 0 (DNA-Binding Proteins); 0 (GUN1 protein, Arabidopsis); 0 (HSFA2 protein, Arabidopsis); 0 (HSP70 Heat-Shock Proteins); 0 (Heat Shock Transcription Factors); 0 (Heat-Shock Proteins); 0 (Hsp100 protein, Arabidopsis); 0 (Molecular Chaperones); 0 (Plant Proteins); 0 (Transcription Factors); BOD072YW0F (Lincomycin); EC 3.4.21.92 (Endopeptidase Clp)


  3 / 1002 MEDLINE  
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PMID:28760849
Autor:Gerth U; Krieger E; Zühlke D; Reder A; Völker U; Hecker M
Endereço:Institute of Microbiology, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany Ulf.Gerth@uni-greifswald.de.
Título:Stability of Proteins Out of Service: the GapB Case of Bacillus subtilis.
Fonte:J Bacteriol; 199(20), 2017 Oct 15.
ISSN:1098-5530
País de publicação:United States
Idioma:eng
Resumo:possesses two glyceraldehyde-3-phosphate dehydrogenases with opposite roles, the glycolytic NAD-dependent GapA and the NADP-dependent GapB enzyme, which is exclusively required during gluconeogenesis but not active under conditions promoting glycolysis. We propose that proteins that are no longer needed will be recognized and proteolyzed by Clp proteases and thereby recycled. To test this postulation, we analyzed the stability of the glycolytic enzyme GapA and the gluconeogenetic enzyme GapB in the presence and absence of glucose. It turned out that GapA remained rather stable under both glycolytic and gluconeogenetic conditions. In contrast, the gluconeogenetic enzyme GapB was degraded after a shift from malate to glucose (i.e., from gluconeogenesis to glycolysis), displaying an estimated half-life of approximately 3 h. Comparative pulse-chase labeling and immunoprecipitation experiments of the wild-type strain and isogenic mutants identified the ATP-dependent ClpCP protease as the enzyme responsible for the degradation of GapB. However, arginine protein phosphorylation, which was recently described as a general tagging mechanism for protein degradation, did not seem to play a role in GapB proteolysis, because GapB was also degraded in a mutant, lacking arginine kinase, in the same manner as in the wild type. GapB, the NADP-dependent glyceraldehyde-3-phosphosphate dehydrogenase, is essential for under gluconeogenetic conditions. However, after a shift to glycolytic conditions, GapB loses its physiological function within the cell and becomes susceptible to degradation, in contrast to GapA, the glycolytic NAD-dependent glyceraldehyde-3-phosphate dehydrogenase, which remains stable under glycolytic and gluconeogenetic conditions. Subsequently, GapB is proteolyzed in a ClpCP-dependent manner. According to our data, the arginine kinase McsB is not involved as adaptor protein in this process. ClpCP appears to be in charge in the removal of inoperable enzymes in , which is a strictly regulated process in which the precise recognition mechanism(s) remains to be identified.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:EC 1.2.1.13 (Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating)); EC 3.4.21.92 (Endopeptidase Clp); IY9XDZ35W2 (Glucose)


  4 / 1002 MEDLINE  
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PMID:28566324
Autor:Quirós PM; Prado MA; Zamboni N; D'Amico D; Williams RW; Finley D; Gygi SP; Auwerx J
Endereço:Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Título:Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
Fonte:J Cell Biol; 216(7):2027-2045, 2017 Jul 03.
ISSN:1540-8140
País de publicação:United States
Idioma:eng
Resumo:Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans-expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (ATF4 protein, human); 0 (Atf4 protein, mouse); 0 (Mitochondrial Proteins); 0 (Proteome); 0 (Ribosomal Proteins); 145891-90-3 (Activating Transcription Factor 4); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.92 (CLPP protein, mouse); EC 3.4.21.92 (Endopeptidase Clp); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.4.99.- (ATP dependent 26S protease)


  5 / 1002 MEDLINE  
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PMID:28507098
Autor:Joshi KK; Sutherland M; Chien P
Endereço:From the Department of Biochemistry and Molecular Biology and.
Título:Cargo engagement protects protease adaptors from degradation in a substrate-specific manner.
Fonte:J Biol Chem; 292(26):10973-10982, 2017 Jun 30.
ISSN:1083-351X
País de publicação:United States
Idioma:eng
Resumo:Protein degradation in bacteria is a highly controlled process involving proteolytic adaptors that regulate protein degradation during cell cycle progression or during stress responses. Many adaptors work as scaffolds that selectively bind cargo and tether substrates to their cognate proteases to promote substrate destruction, whereas others primarily activate the target protease. Because adaptors must bind their cognate protease, all adaptors run the risk of being recognized by the protease as substrates themselves, a process that could limit their effectiveness. Here we use purified proteins in a reconstituted system and studies to show that adaptors of the ClpXP protease are readily degraded but that cargo binding inhibits this degradation. We found that this principle extends across several adaptor systems, including the hierarchical adaptors that drive the bacterial cell cycle and the quality control adaptor SspB. We also found that the ability of a cargo to protect its adaptor is adaptor substrate-specific, as adaptors with artificial degradation tags were not protected even though cargo binding is unaffected. Our work points to an optimization of inherent adaptor degradation and cargo binding that ensures that robust adaptor activity is maintained when high amounts of substrate must be delivered and that adaptors can be eliminated when their tasks have been completed.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Bacterial Proteins); 0 (Carrier Proteins); EC 3.4.21.92 (Endopeptidase Clp)


  6 / 1002 MEDLINE  
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PMID:28431231
Autor:Yeom J; Wayne KJ; Groisman EA
Endereço:Department of Microbial Pathogenesis, Yale School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Título:Sequestration from Protease Adaptor Confers Differential Stability to Protease Substrate.
Fonte:Mol Cell; 66(2):234-246.e5, 2017 Apr 20.
ISSN:1097-4164
País de publicação:United States
Idioma:eng
Resumo:According to the N-end rule, the N-terminal residue of a protein determines its stability. In bacteria, the adaptor ClpS mediates proteolysis by delivering substrates bearing specific N-terminal residues to the protease ClpAP. We now report that the Salmonella adaptor ClpS binds to the N terminus of the regulatory protein PhoP, resulting in PhoP degradation by ClpAP. We establish that the PhoP-activated protein MgtC protects PhoP from degradation by outcompeting ClpS for binding to PhoP. MgtC appears to act exclusively on PhoP, as it did not alter the stability of a different ClpS-dependent ClpAP substrate. Removal of five N-terminal residues rendered PhoP stability independent of both the clpS and mgtC genes. By preserving PhoP protein levels, MgtC enables normal temporal transcription of PhoP-activated genes. The identified mechanism provides a simple means to spare specific substrates from an adaptor-dependent protease.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Bacterial Proteins); 0 (Cation Transport Proteins); 125360-99-8 (PhoP protein, Bacteria); EC 3.4.21.92 (Endopeptidase Clp); EC 3.6.1.- (MgtC protein, Salmonella typhimurium)


  7 / 1002 MEDLINE  
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PMID:28375422
Autor:Malik IT; Brötz-Oesterhelt H
Endereço:Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Germany. heike.broetz-oesterhelt@uni-tuebingen.de.
Título:Conformational control of the bacterial Clp protease by natural product antibiotics.
Fonte:Nat Prod Rep; 34(7):815-831, 2017 Jul 06.
ISSN:1460-4752
País de publicação:England
Idioma:eng
Resumo:Covering: up to 2017The bacterial Clp protease is a highly conserved and structurally versatile machine. It has gained a lot of recognition during the last decade as a novel antibacterial drug target with an unprecedented mechanism of action. Due to its complexity, there are distinct means of interfering with its natural functions and several compounds targeting this machine have been identified. In this review, we summarize the current state of knowledge about natural products deregulating Clp proteolysis, a crucial and delicate process within the cell. Among those, acyldepsipeptide antibiotics of the ADEP class (ADEPs) are characterized best. The molecular mechanism of ADEP-mediated deregulation sheds light on the inner workings of the Clp protease.
Tipo de publicação: JOURNAL ARTICLE; REVIEW
Nome de substância:0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Biological Products); 0 (Depsipeptides); EC 3.4.21.92 (Endopeptidase Clp)


  8 / 1002 MEDLINE  
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PMID:28335002
Autor:Bury K; Wegrzyn K; Konieczny I
Endereço:Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-308 Gdansk, Poland.
Título:Handcuffing reversal is facilitated by proteases and replication initiator monomers.
Fonte:Nucleic Acids Res; 45(7):3953-3966, 2017 Apr 20.
ISSN:1362-4962
País de publicação:England
Idioma:eng
Resumo:Specific nucleoprotein complexes are formed strictly to prevent over-initiation of DNA replication. An example of those is the so-called handcuff complex, in which two plasmid molecules are coupled together with plasmid-encoded replication initiation protein (Rep). In this work, we elucidate the mechanism of the handcuff complex disruption. In vitro tests, including dissociation progress analysis, demonstrate that the dimeric variants of plasmid RK2 replication initiation protein TrfA are involved in assembling the plasmid handcuff complex which, as we found, reveals high stability. Particular proteases, namely Lon and ClpAP, disrupt the handcuff by degrading TrfA, thus affecting plasmid stability. Moreover, our data demonstrate that TrfA monomers are able to dissociate handcuffed plasmid molecules. Those monomers displace TrfA molecules, which are involved in handcuff formation, and through interaction with the uncoupled plasmid replication origins they re-initiate DNA synthesis. We discuss the relevance of both Rep monomers and host proteases for plasmid maintenance under vegetative and stress conditions.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (DNA, Bacterial); 0 (Escherichia coli Proteins); 0 (Nucleoproteins); 0 (TrfA protein, E coli); EC 3.4.21.53 (ClpA protease, E coli); EC 3.4.21.53 (Lon protein, E coli); EC 3.4.21.53 (Protease La); EC 3.4.21.92 (ClpP protease, E coli); EC 3.4.21.92 (Endopeptidase Clp)


  9 / 1002 MEDLINE  
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PMID:28228329
Autor:Wurm P; Tutz S; Mutsam B; Vorkapic D; Heyne B; Grabner C; Kleewein K; Halscheidt A; Schild S; Reidl J
Endereço:University of Graz, Institute of Molecular Biosciences, Molecular Enzymology and Physiology, Humboldtstraße 50, A-8010 Graz, Austria.
Título:Stringent factor and proteolysis control of sigma factor RpoS expression in Vibrio cholerae.
Fonte:Int J Med Microbiol; 307(3):154-165, 2017 Apr.
ISSN:1618-0607
País de publicação:Germany
Idioma:eng
Resumo:Vibrio cholerae can colonize the gastrointestinal track of humans and cause the disease cholera. During colonization, the alternative sigma factor, RpoS, controls a process known as "mucosal escape response," defining a specific spatial and temporal response and effecting chemotaxis and motility. In this report, the expression and proteolytic control of RpoS in V. cholerae was characterized. To date, aspects of proteolysis control, the involved components, and proteolysis regulation have not been addressed for RpoS in V. cholerae. Similar to Escherichia coli, we find that the RpoS protein is subjected to regulated intracellular proteolysis, which is mediated by homologues of the proteolysis-targeting factor RssB and the protease complex ClpXP. As demonstrated, RpoS expression transiently peaks after cells are shifted from rich to minimal growth medium. This peak level is dependent on (p)ppGpp-activated rpoS transcription and controlled RpoS proteolysis. The RpoS peak level also correlates with induction of a chemotaxis gene, encoding a methyl-accepting chemotaxis protein, earlier identified to belong to the mucosal escape response pathway. These results suggest that the RpoS expression peak is linked to (p)ppGpp alarmone increase, leading to enhanced motility and chemotaxis, and possibly contributing to the mucosal escape response.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Bacterial Proteins); 0 (Culture Media); 0 (Sigma Factor); 0 (sigma factor KatF protein, Bacteria); EC 2.7.6.5 (GTP Pyrophosphokinase); EC 3.4.21.92 (Endopeptidase Clp)


  10 / 1002 MEDLINE  
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PMID:28223361
Autor:Baytshtok V; Chen J; Glynn SE; Nager AR; Grant RA; Baker TA; Sauer RT
Endereço:From the Department of Biology and.
Título:Covalently linked HslU hexamers support a probabilistic mechanism that links ATP hydrolysis to protein unfolding and translocation.
Fonte:J Biol Chem; 292(14):5695-5704, 2017 Apr 07.
ISSN:1083-351X
País de publicação:United States
Idioma:eng
Resumo:The HslUV proteolytic machine consists of HslV, a double-ring self-compartmentalized peptidase, and one or two AAA+ HslU ring hexamers that hydrolyze ATP to power the unfolding of protein substrates and their translocation into the proteolytic chamber of HslV. Here, we use genetic tethering and disulfide bonding strategies to construct HslU pseudohexamers containing mixtures of ATPase active and inactive subunits at defined positions in the hexameric ring. Genetic tethering impairs HslV binding and degradation, even for pseudohexamers with six active subunits, but disulfide-linked pseudohexamers do not have these defects, indicating that the peptide tether interferes with HslV interactions. Importantly, pseudohexamers containing different patterns of hydrolytically active and inactive subunits retain the ability to unfold protein substrates and/or collaborate with HslV in their degradation, supporting a model in which ATP hydrolysis and linked mechanical function in the HslU ring operate by a probabilistic mechanism.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (ClpYQ protease, E coli); 0 (Escherichia coli Proteins); 8L70Q75FXE (Adenosine Triphosphate); EC 3.4.21.92 (Endopeptidase Clp)



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