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Multi-metal Restriction by Calprotectin Impacts De Novo Flavin Biosynthesis in Acinetobacter baumannii.
Wang J, Lonergan ZR, Gonzalez-Gutierrez G, Nairn BL, Maxwell CN, Zhang Y, Andreini C, Karty JA, Chazin WJ, Trinidad JC, Skaar EP, Giedroc DP
(2019) Cell Chem Biol 26: 745-755.e7
MeSH Terms: Acinetobacter baumannii, Bacterial Proteins, Chromatography, High Pressure Liquid, Flavins, Heat-Shock Proteins, Iron, Leukocyte L1 Antigen Complex, Metallochaperones, Proteome, Tandem Mass Spectrometry, Zinc
Show Abstract · Added March 26, 2019
Calprotectin (CP) inhibits bacterial viability through extracellular chelation of transition metals. However, how CP influences general metabolism remains largely unexplored. We show here that CP restricts bioavailable Zn and Fe to the pathogen Acinetobacter baumannii, inducing an extensive multi-metal perturbation of cellular physiology. Proteomics reveals severe metal starvation, and a strain lacking the candidate Zn metallochaperone ZigA possesses altered cellular abundance of multiple essential Zn-dependent enzymes and enzymes in de novo flavin biosynthesis. The ΔzigA strain exhibits decreased cellular flavin levels during metal starvation. Flavin mononucleotide provides regulation of this biosynthesis pathway, via a 3,4-dihydroxy-2-butanone 4-phosphate synthase (RibB) fusion protein, RibBX, and authentic RibB. We propose that RibBX ensures flavin sufficiency under CP-induced Fe limitation, allowing flavodoxins to substitute for Fe-ferredoxins as cell reductants. These studies elucidate adaptation to nutritional immunity and define an intersection between metallostasis and cellular metabolism in A. baumannii.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Nanotechnology Enabled Modulation of Signaling Pathways Affects Physiologic Responses in Intact Vascular Tissue.
Hocking KM, Evans BC, Komalavilas P, Cheung-Flynn J, Duvall CL, Brophy CM
(2019) Tissue Eng Part A 25: 416-426
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Blood Vessels, Calcium, Gene Silencing, Heat-Shock Proteins, Humans, Micelles, Muscle Contraction, Muscle, Smooth, Nanoparticles, Nanotechnology, Peptides, Polymerization, RNA, Small Interfering, Rats, Signal Transduction, Static Electricity
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - Subarachnoid hemorrhage (SAH) is associated with vasospasm that is refractory to traditional vasodilators, and inhibition of vasospasm after SAH remains a large unmet clinical need. SAH causes changes in the phosphorylation state of the small heat shock proteins (HSPs), HSP20 and HSP27, in the vasospastic vessels. In this study, the levels of HSP27 and HSP20 were manipulated using nanotechnology to mimic the intracellular phenotype of SAH-induced vasospasm, and the effect of this manipulation was tested on vasomotor responses in intact tissues. This work provides insight into potential therapeutic targets for the development of more effective treatments for SAH induced vasospasm.
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19 MeSH Terms
Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.
Veri AO, Miao Z, Shapiro RS, Tebbji F, O'Meara TR, Kim SH, Colazo J, Tan K, Vyas VK, Whiteway M, Robbins N, Wong KH, Cowen LE
(2018) PLoS Genet 14: e1007270
MeSH Terms: Blotting, Western, Candida albicans, Chromatin Immunoprecipitation, Genes, Fungal, HSP90 Heat-Shock Proteins, Heat Shock Transcription Factors, Morphogenesis, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Temperature, Virulence
Show Abstract · Added November 7, 2019
The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.
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The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer.
Chen KC, Qu S, Chowdhury S, Noxon IC, Schonhoft JD, Plate L, Powers ET, Kelly JW, Lander GC, Wiseman RL
(2017) EMBO J 36: 2296-2309
MeSH Terms: Cell Line, Endoplasmic Reticulum, Epithelial Cells, HSP40 Heat-Shock Proteins, Humans, Microscopy, Electron, Protein Interaction Mapping, Protein Multimerization
Show Abstract · Added March 3, 2020
ERdj3/DNAJB11 is an endoplasmic reticulum (ER)-targeted HSP40 co-chaperone that performs multifaceted functions involved in coordinating ER and extracellular proteostasis. Here, we show that ERdj3 assembles into a native tetramer that is distinct from the dimeric structure observed for other HSP40 co-chaperones. An electron microscopy structural model of full-length ERdj3 shows that these tetramers are arranged as a dimer of dimers formed by distinct inter-subunit interactions involving ERdj3 domain II and domain III Targeted deletion of residues 175-190 within domain II renders ERdj3 a stable dimer that is folded and efficiently secreted from mammalian cells. This dimeric ERdj3 shows impaired substrate binding both in the ER and extracellular environments and reduced interactions with the ER HSP70 chaperone BiP. Furthermore, we show that overexpression of dimeric ERdj3 exacerbates ER stress-dependent reductions in the secretion of a destabilized, aggregation-prone protein and increases its accumulation as soluble oligomers in extracellular environments. These results reveal ERdj3 tetramerization as an important structural framework for ERdj3 functions involved in coordinating ER and extracellular proteostasis in the presence and absence of ER stress.
© 2017 The Authors.
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MeSH Terms
Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.
Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW
(2016) Nat Med 22: 800-6
MeSH Terms: Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Body Composition, Brain, Carbon Radioisotopes, Deoxyglucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Ependymoglial Cells, Fibroblast Growth Factor 1, Forkhead Box Protein O1, Glucose Tolerance Test, Heart, Heat-Shock Proteins, Hyperglycemia, Hypothalamus, Injections, Intraventricular, Liver, Male, Mice, Mice, Knockout, Mice, Obese, Muscle, Skeletal, Myocardium, Neoplasm Proteins, Proto-Oncogene Proteins c-fos, Rats, Rats, Zucker, Real-Time Polymerase Chain Reaction, Receptor, Insulin, Remission Induction
Show Abstract · Added May 16, 2019
Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.
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Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor.
Banathy A, Cheung-Flynn J, Goleniewska K, Boyd KL, Newcomb DC, Peebles RS, Komalavilas P
(2016) Am J Respir Cell Mol Biol 55: 225-33
MeSH Terms: Actins, Adrenergic beta-2 Receptor Antagonists, Allergens, Animals, Bronchial Hyperreactivity, Carbachol, Cell Movement, Constriction, HSP20 Heat-Shock Proteins, Humans, Inflammation, Lung, Mice, Muscle Contraction, Muscle Relaxation, Muscle, Smooth, Myocytes, Smooth Muscle, Ovalbumin, Peptides, Receptors, Adrenergic, beta-2, Stress Fibers, Sus scrofa
Show Abstract · Added March 3, 2020
Severe bronchospasm refractory to β-agonists is a challenging aspect of asthma therapy, and novel therapeutics are needed. β-agonist-induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of the small heat shock-related protein (HSP) 20. We hypothesized that a transducible phosphopeptide mimetic of HSP20 (P20 peptide) causes relaxation of human ASM (HASM) by interacting with target(s) downstream of the β2-adrenergic receptor (β2AR) pathway. The effect of the P20 peptide on ASM contractility was determined in human and porcine ASM using a muscle bath. The effect of the P20 peptide on filamentous actin dynamics and migration was examined in intact porcine ASM and cultured primary HASM cells. The efficacy of the P20 peptide in vivo on airway hyperresponsiveness (AHR) was determined in an ovalbumin (OVA) sensitization and challenge murine model of allergic airway inflammation. P20 peptide caused dose-dependent relaxation of carbachol-precontracted ASM and blocked carbachol-induced contraction. The β2AR inhibitor, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551), abrogated isoproterenol but not P20 peptide-mediated relaxation. The P20 peptide decreased filamentous actin levels in intact ASM, disrupted stress fibers, and inhibited platelet-derived growth factor-induced migration of HASM cells. The P20 peptide treatment reduced methacholine-induced AHR in OVA mice without affecting the inflammatory response. These results suggest that the P20 peptide decreased airway constriction and disrupted stress fibers through regulation of the actin cytoskeleton downstream of β2AR. Thus, the P20 peptide may be a potential therapeutic for asthma refractory to β-agonists.
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Biochemical and Proteomic Analysis of Ubiquitination of Hsc70 and Hsp70 by the E3 Ligase CHIP.
Soss SE, Rose KL, Hill S, Jouan S, Chazin WJ
(2015) PLoS One 10: e0128240
MeSH Terms: HSC70 Heat-Shock Proteins, Humans, Proteomics, Recombinant Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added February 5, 2016
The E3 ubiquitin ligase CHIP is involved in protein triage, serving as a co-chaperone for refolding as well as catalyzing ubiquitination of substrates. CHIP functions with both the stress induced Hsp70 and constitutive Hsc70 chaperones, and also plays a role in maintaining their balance in the cell. When the chaperones carry no client proteins, CHIP catalyzes their polyubiquitination and subsequent proteasomal degradation. Although Hsp70 and Hsc70 are highly homologous in sequence and similar in structure, CHIP mediated ubiquitination promotes degradation of Hsp70 with a higher efficiency than for Hsc70. Here we report a detailed and systematic investigation to characterize if there are significant differences in the CHIP in vitro ubiquitination of human Hsp70 and Hsc70. Proteomic analysis by mass spectrometry revealed that only 12 of 39 detectable lysine residues were ubiquitinated by UbcH5a in Hsp70 and only 16 of 45 in Hsc70. The only conserved lysine identified as ubiquitinated in one but not the other heat shock protein was K159 in Hsc70. Ubiquitination assays with K-R ubiquitin mutants showed that multiple Ub chain types are formed and that the distribution is different for Hsp70 versus Hsc70. CHIP ubiquitination with the E2 enzyme Ube2W is predominantly directed to the N-terminal amine of the substrate; however, some internal lysine modifications were also detected. Together, our results provide a detailed view of the differences in CHIP ubiquitination of these two very similar proteins, and show a clear example where substantial differences in ubiquitination can be generated by a single E3 ligase in response to not only different E2 enzymes but subtle differences in the substrate.
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8 MeSH Terms
Tumor-secreted Hsp90 subverts polycomb function to drive prostate tumor growth and invasion.
Nolan KD, Franco OE, Hance MW, Hayward SW, Isaacs JS
(2015) J Biol Chem 290: 8271-82
MeSH Terms: Animals, Antigens, CD, Cadherins, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression, Gene Expression Regulation, Neoplastic, HEK293 Cells, HSP90 Heat-Shock Proteins, Humans, MAP Kinase Signaling System, Male, Mice, SCID, Neoplasm Invasiveness, Neoplasm Transplantation, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Prostatic Neoplasms, Tumor Burden
Show Abstract · Added February 19, 2015
Prostate cancer remains the second highest contributor to male cancer-related lethality. The transition of a subset of tumors from indolent to invasive disease is associated with a poor clinical outcome. Activation of the epithelial to mesenchymal transition (EMT) genetic program is a major risk factor for cancer progression. We recently reported that secreted extracellular Hsp90 (eHsp90) initiates EMT in prostate cancer cells, coincident with its enhanced expression in mesenchymal models. Our current work substantially extended these findings in defining a pathway linking eHsp90 signaling to EZH2 function, a methyltransferase of the Polycomb repressor complex. EZH2 is also implicated in EMT activation, and its up-regulation represents one of the most frequent epigenetic alterations during prostate cancer progression. We have now highlighted a novel epigenetic function for eHsp90 via its modulation of EZH2 expression and activity. Mechanistically, eHsp90 initiated sustained activation of MEK/ERK, a signal critical for facilitating EZH2 transcriptional up-regulation and recruitment to the E-cadherin promoter. We further demonstrated that an eHsp90-EZH2 pathway orchestrates an expanded repertoire of EMT-related events including Snail and Twist expression, tumor cell motility, and anoikis resistance. To evaluate the role of eHsp90 in vivo, eHsp90 secretion was stably enforced in a prostate cancer cell line resembling indolent disease. Remarkably, eHsp90 was sufficient to induce tumor growth, suppress E-cadherin, and initiate localized invasion, events that are exquisitely dependent upon EZH2 function. In summary, our findings illuminate a hitherto unknown epigenetic function for eHsp90 and support a model wherein tumor eHsp90 functions as a rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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21 MeSH Terms
Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.
Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, Shah B, Sharma S, Chang JC, Melnick AM, Hiebert S, Bhalla KN
(2014) Oncotarget 5: 5637-50
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cell Line, Tumor, Checkpoint Kinase 1, Cisplatin, DNA Damage, Drug Synergism, Enzyme Inhibitors, Female, Gene Knockdown Techniques, HSP90 Heat-Shock Proteins, HeLa Cells, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Indoles, MCF-7 Cells, Mice, Panobinostat, Poly(ADP-ribose) Polymerase Inhibitors, Protein Kinases, Reactive Oxygen Species, Triple Negative Breast Neoplasms, Vorinostat, Xenograft Model Antitumor Assays
Show Abstract · Added September 28, 2015
There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.
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28 MeSH Terms
Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Escott-Price V, Bellenguez C, Wang LS, Choi SH, Harold D, Jones L, Holmans P, Gerrish A, Vedernikov A, Richards A, DeStefano AL, Lambert JC, Ibrahim-Verbaas CA, Naj AC, Sims R, Jun G, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Denning N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Schmidt H, Kunkle B, Dunstan ML, Vronskaya M, United Kingdom Brain Expression Consortium, Johnson AD, Ruiz A, Bihoreau MT, Reitz C, Pasquier F, Hollingworth P, Hanon O, Fitzpatrick AL, Buxbaum JD, Campion D, Crane PK, Baldwin C, Becker T, Gudnason V, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Hernández I, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MJ, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuinness B, Larson EB, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, George-Hyslop PS, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Garcia FS, Fox NC, Hardy J, Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Scarpini E, Bonuccelli U, Mancuso M, Siciliano G, Moebus S, Mecocci P, Zompo MD, Maier W, Hampel H, Pilotto A, Frank-García A, Panza F, Solfrizzi V, Caffarra P, Nacmias B, Perry W, Mayhaus M, Lannfelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltunen M, Martin ER, Schmidt R, Rujescu D, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Haines JL, Lathrop M, Pericak-Vance MA, Launer LJ, Van Broeckhoven C, Farrer LA, van Duijn CM, Ramirez A, Seshadri S, Schellenberg GD, Amouyel P, Williams J, Cardiovascular Health Study (CHS)
(2014) PLoS One 9: e94661
MeSH Terms: Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell
Show Abstract · Added December 10, 2014
BACKGROUND - Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
PRINCIPAL FINDINGS - In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.
SIGNIFICANCE - The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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8 MeSH Terms