scholarly journals Transient Hsp90 suppression promotes a heritable change in protein translation

2018 ◽  
Author(s):  
Peter Tsvetkov ◽  
Zarina Brune ◽  
Timothy J. Eisen ◽  
Sven Heinrich ◽  
Greg A. Newby ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Heat Shock Protein 90 ◽  
Protein Translation ◽  
Translation Regulation ◽  
Hsp90 Inhibition ◽  
Transient Loss ◽  
Hsp90 Chaperone ◽  
Physical Interactions ◽  
Heritable Change

The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a unique role promoting the evolution of new heritable traits. To investigate the role of Hsp90 in modulating protein synthesis, we screened more than 1200 proteins involved in mRNA regulation for physical interactions with Hsp90 in human cells. Among the top hits was CPEB2, which strongly binds Hsp90 via its prion domain, reminiscent of the prion-like regulation of translation of Aplysia CPEB. In a yeast model of CPEB prion-dependent translation regulation, transient inhibition of Hsp90 amplified CPEB2 prion activity and resulted in persistent translation of the CPEB reporter. Remarkably, inhibition of Hsp90 was sufficient to induce a heritable change in protein translation that persisted for 30 generations, even in the absence of exogenous CPEB. Although we identified a variety of perturbations that enhanced translation of the reporter, only Hsp90 inhibition led to persistent activation. Thus, transient loss of Hsp90 function leads to the non-genetic inheritance of a novel translational state. We propose that, in addition to sculpting the conformational landscape of the proteome, Hsp90 promotes phenotypic variation by modulating protein synthesis.

InTERTesting association between telomerase, mTOR and phytochemicals

2012 ◽  
Vol 14 ◽  
Author(s):  
Tabetha Sundin ◽  
Patricia Hentosh
Keyword(s):  
Dna Sequences ◽  
Mammalian Target Of Rapamycin ◽  
Heat Shock Protein 90 ◽  
Protein Translation ◽  
Telomerase Activity ◽  
Gene Coding ◽  
Functional Complex ◽  
Telomerase Regulation ◽  
Rate Limiting

Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase – the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats – is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase – the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.

scholarly journals Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

2017 ◽  
Vol 114 (22) ◽  
pp. E4370-E4379 ◽  
Author(s):  
Jang-Hyun Oh ◽  
Ju-Yeon Hyun ◽  
Alexander Varshavsky
Keyword(s):  
Heat Shock Protein 90 ◽  
Mitotic Checkpoint ◽  
Protein Homeostasis ◽  
Wild Type ◽  
Binding Assays ◽  
C Terminus ◽  
Ubiquitin Binding ◽  
Hsp90 Chaperone ◽  
Split Ubiquitin

We found that the heat shock protein 90 (Hsp90) chaperone system of the yeast Saccharomyces cerevisiae is greatly impaired in naa10Δ cells, which lack the NatA Nα-terminal acetylase (Nt-acetylase) and therefore cannot N-terminally acetylate a majority of normally N-terminally acetylated proteins, including Hsp90 and most of its cochaperones. Chk1, a mitotic checkpoint kinase and a client of Hsp90, was degraded relatively slowly in wild-type cells but was rapidly destroyed in naa10Δ cells by the Arg/N-end rule pathway, which recognized a C terminus-proximal degron of Chk1. Diverse proteins (in addition to Chk1) that are shown here to be targeted for degradation by the Arg/N-end rule pathway in naa10Δ cells include Kar4, Tup1, Gpd1, Ste11, and also, remarkably, the main Hsp90 chaperone (Hsc82) itself. Protection of Chk1 by Hsp90 could be overridden not only by ablation of the NatA Nt-acetylase but also by overexpression of the Arg/N-end rule pathway in wild-type cells. Split ubiquitin-binding assays detected interactions between Hsp90 and Chk1 in wild-type cells but not in naa10Δ cells. These and related results revealed a major role of Nt-acetylation in the Hsp90-mediated protein homeostasis, a strong up-regulation of the Arg/N-end rule pathway in the absence of NatA, and showed that a number of Hsp90 clients are previously unknown substrates of the Arg/N-end rule pathway.

scholarly journals Role of PKR in the Inhibition of Proliferation and Translation by Polycystin-1

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Yan Tang ◽  
Guang Shi ◽  
JungWoo Yang ◽  
Wang Zheng ◽  
Jingfeng Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Synthesis ◽  
Kinase Activity ◽  
Protein Translation ◽  
Dominant Negative ◽  
Inhibition Of Proliferation ◽  
Proliferation And Apoptosis ◽  
Autosomal Dominant Polycystic Kidney ◽  
Underlying Mechanisms

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in the PKD1 (~85%) or PKD2 (~15%) gene which, respectively, encode polycystin-1 (PC1) and polycystin-2 (PC2). How PC1 regulates cell proliferation and apoptosis has been studied for decades but the underlying mechanisms remain controversial. Protein kinase RNA-activated (PKR) is activated by interferons or double-stranded RNAs, inhibits protein translation, and induces cell apoptosis. In a previous study, we found that PC1 reduces apoptosis through suppressing the PKR/eIF2α signaling. Whether and how PKR is involved in PC1-inhibited proliferation and protein synthesis remains unknown. Here we found that knockdown of PKR abolishes PC1-inhibited proliferation and translation. Because suppressed PKR-eIF2α signaling/activity by PC1 would stimulate, rather than inhibit, the proliferation and translation, we examined the effect of dominant negative PKR mutant K296R that has no kinase activity and found that it enhances the inhibition of proliferation and translation by PC1. Thus, our study showed that inhibition of cell proliferation and protein synthesis by PC1 is mediated by the total expression but not the kinase activity of PKR, possibly through physical association.

scholarly journals Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus

2021 ◽  
Vol 22 (4) ◽  
pp. 2020
Author(s):  
Iga Dalidowska ◽  
Olga Gazi ◽  
Dorota Sulejczak ◽  
Maciej Przybylski ◽  
Pawel Bieganowski
Keyword(s):  
Mrna Level ◽  
Heat Shock Protein 90 ◽  
Human Adenovirus ◽  
Hsp90 Inhibitor ◽  
Hsp90 Inhibition ◽  
Early Protein ◽  
Fold Reduction ◽  
Hsp90 Chaperone ◽  
Adenovirus 5 ◽  
E1a Protein

Adenovirus infections tend to be mild, but they may pose a serious threat for young and immunocompromised individuals. The treatment is complicated because there are no approved safe and specific drugs for adenovirus infections. Here, we present evidence that 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 chaperone, decreases the rate of human adenovirus 5 (HAdV-5) replication in cell cultures by 95%. 17-AAG inhibited the transcription of early and late genes of HAdV-5, replication of viral DNA, and expression of viral proteins. 6 h after infection, Hsp90 inhibition results in a 6.3-fold reduction of the newly synthesized E1A protein level without a decrease in the E1A mRNA level. However, the Hsp90 inhibition does not increase the decay rate of the E1A protein that was constitutively expressed in the cell before exposure to the inhibitor. The co-immunoprecipitation proved that E1A protein interacted with Hsp90. Altogether, the presented results show, for the first time. that Hsp90 chaperones newly synthesized, but not mature, E1A protein. Because E1A serves as a transcriptional co-activator of adenovirus early genes, the anti-adenoviral activity of the Hsp90 inhibitor might be explained by the decreased E1A level.

scholarly journals Endurance exercise decreases protein synthesis and ER-mitochondria contacts in mouse skeletal muscle

2019 ◽  
Vol 127 (5) ◽  
pp. 1297-1306 ◽  
Author(s):  
Audrey Merle ◽  
Maxence Jollet ◽  
Florian A. Britto ◽  
Bénédicte Goustard ◽  
Nadia Bendridi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Energy Demand ◽  
Protein Translation ◽  
Strong Increase ◽  
Hindlimb Muscles

Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57Bl/6J mice ran at 12 m/min for 45 min or at 12 m/min for the first 25 min followed by a progressive increase in velocity up to 20 m/min for the last 20 min. Animals were injected intraperitoneally with 40 nmol/g of body weight of puromycin and euthanized by cervical dislocation immediately after exercise cessation. Analysis of gastrocnemius, plantaris, quadriceps, soleus, and tibialis anterior muscles revealed a decrease in protein translation assessed by puromycin incorporation, without significant differences among muscles or running intensities. The reduction of protein synthesis was associated with a marked inhibition of mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, a mechanism consistent with reduced translation initiation. A slight activation of AMP-activated protein kinase consecutive to the running session was measured but did not correlate with mTORC1 inhibition. More importantly, exercise resulted in a strong upregulation of regulated in development and DNA damage 1 (REDD1) protein and gene expressions, whereas transcriptional regulation of other recognized exercise-induced genes ( IL-6, kruppel-like factor 15, and regulator of calcineurin 1) did not change. Consistently with the recently discovered role of REDD1 on mitochondria-associated membranes, we observed a decrease in mitochondria-endoplasmic reticulum interaction following exercise. Collectively, these data raise questions concerning the role of mitochondria-associated endoplasmic reticulum membrane disruption in the regulation of muscle proteostasis during exercise and, more generally, in cell adaptation to metabolic stress. NEW & NOTEWORTHY How muscles regulate protein synthesis to cope with the energy demand during contraction is poorly documented. Moreover, it is unknown whether protein translation is differentially affected among mouse hindlimb muscles under different physiological exercise modalities. We showed here that 45 min of running decreases puromycin incorporation similarly in 5 different mouse muscles. This decrease was associated with a strong increase in regulated in development and DNA damage 1 protein expression and a significant disruption of the mitochondria and sarcoplasmic reticulum interaction.

scholarly journals Protein synthesis regulation by leucine

2010 ◽  
Vol 46 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Daiana Vianna ◽  
Gabriela Fullin Resende Teodoro ◽  
Francisco Leonardo Torres-Leal ◽  
Julio Tirapegui
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Mrna Translation ◽  
Protein Translation ◽  
Cellular Effects ◽  
Cellular Processes ◽  
High Protein Diets

In vivo and in vitro studies have demonstrated that high protein diets affect both protein synthesis and regulation of several cellular processes. The role of amino acids as substrate for protein synthesis has been established in the literature. However, the mechanism by which these amino acids modulate transcription and regulate the mRNA translation via mTOR-dependent signaling pathway has yet to be fully determined. It has been verified that mTOR is a protein responsible for activating a cascade of biochemical intracellular events which result in the activation of the protein translation process. Of the aminoacids, leucine is the most effective in stimulating protein synthesis and reducing proteolysis. Therefore, it promotes a positive nitrogen balance, possibly by favoring the activation of this protein. This amino acid also directly and indirectly stimulates the synthesis and secretion of insulin, enhancing its anabolic cellular effects. Therefore, this review aimed to identify the role of leucine in protein synthesis modulation and to discuss the metabolic aspects related to this aminoacid.

scholarly journals A role of cellular translation regulation associated with toxic Huntingtin protein

2019 ◽  
Author(s):  
Hiranmay Joag ◽  
Vighnesh Ghatpande ◽  
Maitheli Sarkar ◽  
Anshu Raina ◽  
Meghal Desai ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Neurodegenerative Disorder ◽  
Repeat Expansion ◽  
Translation Regulation ◽  
Disease Symptoms ◽  
New Therapies ◽  
Cellular Processes ◽  
Amyloid Aggregates ◽  
Cellular Translation

AbstractHuntington’s disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, its role in translation is not addressed. Here we report pathogenic Htt expression causes protein synthesis deficit in cells. We find a functional prion-like protein, the translation regulator Orb2 to be sequestered by Htt aggregates. Coexpression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 also can be sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction could be one of the contributors in the pathogenesis of HD and new therapies targeting protein synthesis pathways might help alleviate disease symptoms.

scholarly journals The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

2020 ◽  
Author(s):  
Roberto C. Molina-Quiroz ◽  
Andrew Camilli
Keyword(s):  
Protein Synthesis ◽  
Protein Translation ◽  
Synthesis Process ◽  
Phenotypic Trait ◽  
Dependent Manner ◽  
Bacterial Survival ◽  
Persister Cells ◽  
Initiation Of Translation ◽  
Persister Cell

AbstractBacterial persistence is a non-heritable phenotypic trait characterized by a dormant state that leads to tolerance to different antibiotics. Several mechanisms contributing to persister cells generation have been identified. Among these, is the signaling molecule (p)ppGpp, but knowledge of how this molecule regulates persister generation is incomplete. Here, we show an increase of the persister fraction of uropathogenic Escherichia coli (UPEC) that correlates with the time of protein synthesis inhibition and a decrease in the availability of antibiotic target. Specifically, the arrest of translation initiation induces bacterial survival to ampicillin and ciprofloxacin in a (p)ppGpp-dependent manner. These findings support a global mechanism of persister cell generation and establish a regulatory role of the (p)ppGpp molecule in this phenomenon.ImportanceThe study of persister cell formation is relevant because this bacterial subpopulation is involved in the emergence of antibiotic resistance and the generation of chronic infections. A role of the (p)ppGpp molecule in the generation of the persister fraction has been described, but the identification of the regulatory mechanism mediated by this alarmone during protein translation and its contribution to persistence has not been described to date. In this work, we show that (p)ppGpp regulates the generation of persister cells at the initiation of the protein synthesis process in UPEC. Our results also suggest that a (p)ppGpp-dependent regulation of translation, might be a global mechanism for the generation of the persister fraction.

scholarly journals Obligatory role of heat shock protein 90 in iNOS induction

2011 ◽  
Vol 301 (1) ◽  
pp. C227-C233 ◽  
Author(s):  
Suxin Luo ◽  
Tingting Wang ◽  
Honghua Qin ◽  
Han Lei ◽  
Yong Xia
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Inos Expression ◽  
Inos Mrna ◽  
Mrna Transcription ◽  
Hsp90 Inhibition ◽  
Ifn Γ ◽  
Inos Induction

Inducible nitric oxide (NO) synthase (iNOS) plays an important role in cell injury and host defense. While undetectable in normal tissues, iNOS expression is induced by endotoxins and inflammatory cytokines primarily via the IκB kinase/nuclear factor-κB (IKK-NF-κB) and Janus kinase (JAK)-signal transducers and activators of transcription 1 (STAT1) pathways. Our previous studies found that heat shock protein 90 (Hsp90) associates with iNOS, and this association enhances iNOS activity. Here we show that Hsp90 is also essential for iNOS induction. With mouse macrophages, Hsp90 inhibition by geldanamycin or knockdown with small interfering RNA (siRNA) prevented lipopolysaccharide (LPS) or interferon-γ (IFN-γ)-stimulated iNOS protein expression. RT-PCR experiments showed that iNOS mRNA transcription was blocked by Hsp90 inhibition. Radicicol, another Hsp90 inhibitor whose structure is different from that of geldanamycin, also blocked iNOS mRNA transcription. These cell biology findings were confirmed in infarcted myocardium where iNOS expression was markedly attenuated by Hsp90 inhibition in vivo. Intriguingly, further analyses showed that inhibiting Hsp90 had no significant effect on the activation of either IKK-NF-κB or JAK-STAT1 in LPS/IFN-γ-stimulated cells. Neither was the nuclear transport of active NF-κB or STAT1 affected by Hsp90 inhibition. But Hsp90 inhibition markedly reduced the binding of active NF-κB and STAT1 to their DNA elements. Chromatin immunoprecipitation assays confirmed that Hsp90 was essential for NF-κB and STAT1 bindings to iNOS promoters inside cells. These studies reveal that besides acting as an allosteric enhancer, Hsp90 is also required for transcriptional factor binding amid iNOS mRNA transcription. In view of the essential role of Hsp90 in iNOS gene transactivation, targeting Hsp90 may represent a new approach to intervene iNOS expression in diseases.

Sign in / Sign up

Export Citation Format

Share Document