scholarly journals Trypanosoma brucei J-Protein 2 Functionally Co-Operates with the Cytosolic Hsp70 and Hsp70.4 Proteins

2019 ◽  
Vol 20 (23) ◽  
pp. 5843 ◽  
Author(s):  
Stephen John Bentley ◽  
Aileen Boshoff
Keyword(s):  
Heat Shock ◽  
Trypanosoma Brucei ◽  
Therapeutic Strategies ◽  
Type I ◽  
Protein Homeostasis ◽  
African Trypanosomiasis ◽  
Wide Range ◽  
Shock Proteins ◽  
Insight Into ◽  
J Protein

The etiological agent of African trypanosomiasis, Trypanosoma brucei (Tb), has been identified to possess an expanded and diverse group of heat shock proteins, which have been implicated in cytoprotection, differentiation, and subsequently progression and transmission of the disease. Heat shock protein 70 (Hsp70) is a highly conserved and ubiquitous molecular chaperone that is important in maintaining protein homeostasis in the cell. Its function is regulated by a wide range of co-chaperones, and inhibition of these functions and interactions with co-chaperones are emerging as potential therapeutic targets for numerous diseases. This study sought to biochemically characterize the cytosolic TbHsp70 and TbHsp70.4 proteins and to investigate if they functionally co-operate with the Type I J-protein, Tbj2. Expression of TbHsp70 was shown to be heat inducible, while TbHsp70.4 was constitutively expressed. The basal ATPase activities of TbHsp70.4 and TbHsp70 were stimulated by Tbj2. It was further determined that Tbj2 functionally co-operated with TbHsp70 and TbHsp70.4 as the J-protein was shown to stimulate the ability of both proteins to mediate the refolding of chemically denatured β-galactosidase. This study provides further insight into this important class of proteins, which may contribute to the development of new therapeutic strategies to combat African Trypanosomiasis.

scholarly journals Trypanosoma bruceiJ protein 2 functionally cooperates with the cytosolic Hsp70.4 and Hsp70 proteins

2019 ◽  
Author(s):  
Stephen J. Bentley ◽  
Aileen Boshoff
Keyword(s):  
Heat Shock ◽  
Trypanosoma Brucei ◽  
Therapeutic Strategies ◽  
Type I ◽  
Protein Homeostasis ◽  
African Trypanosomiasis ◽  
Wide Range ◽  
Shock Proteins ◽  
Insight Into ◽  
J Protein

AbstractThe etiological agent of African trypanosomiasis,Trypanosoma brucei, has been identified to possess an expanded and diverse group of heat shock proteins, that have been implicated in cytoprotection, differentiation, and subsequently progression and transmission of the disease. Heat shock protein 70 is a highly conserved and ubiquitous molecular chaperone that is important in maintaining protein homeostasis in the cell. Its function is regulated by a wide range of co-chaperones; and inhibition of these functions and interactions with co-chaperones are emerging as potential therapeutic targets for numerous diseases. This study sought to biochemically characterize the cytosolic Hsp70 and Hsp70.4 proteins and to investigate if they form a functional partnership with the Type I J-protein, Tbj2. The cytosolic localisation of the proteins was confirmed by accessing the TrypTag endogenous tagging microscopy database. Expression of TbHsp70 was shown to be heat inducible, whilst TbHsp70.4 was constitutively expressed. The basal ATPase activities of TbHsp70.4 and TbHsp70 were stimulated by Tbj2. It was further determined that Tbj2 forms a functional partnership with TbHsp70 and TbHsp70.4 as the J-protein was shown to stimulate the ability of both proteins to mediate the refolding of chemically denatured β-galactosidase. This study provides further insight into this important class of proteins which may contribute to the development of new therapeutic strategies to combat African Trypanosomiasis.

Expression of heat shock proteins in medulloblastoma

2013 ◽  
Vol 12 (5) ◽  
pp. 452-457 ◽  
Author(s):  
George A. Alexiou ◽  
George Vartholomatos ◽  
Kalliopi Stefanaki ◽  
Amalia Patereli ◽  
Lefkothea Dova ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Significant Positive Correlation ◽  
Large Cell ◽  
Hsp70 Expression ◽  
Ki 67 ◽  
Positive Correlation ◽  
Wide Range ◽  
Shock Proteins ◽  
Multiplex Bead

Object Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis. Methods The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

scholarly journals Daily Supplementation of L-Glutamine in Atrial Fibrillation Patients: The Effect on Heat Shock Proteins and Metabolites

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1729 ◽  
Author(s):  
Roeliene Starreveld ◽  
Kennedy S. Ramos ◽  
Agnes J. Q. M. Muskens ◽  
Bianca J. J. M. Brundel ◽  
Natasja M. S. de Groot
Keyword(s):  
Atrial Fibrillation ◽  
Heat Shock ◽  
Metabolic Pathways ◽  
Serum Levels ◽  
Therapeutic Strategies ◽  
Glutamine Supplementation ◽  
Novel Therapies ◽  
Cardioprotective Effects ◽  
Baseline Levels ◽  
Shock Proteins

Pharmaco-therapeutic strategies of atrial fibrillation (AF) are moderately effective and do not prevent AF onset and progression. Therefore, there is an urgent need to develop novel therapies. Previous studies revealed heat shock protein (HSP)-inducing compounds to mitigate AF onset and progression. Such an HSP inducing compound is L-glutamine. In the current study we investigate the effect of L-glutamine supplementation on serum HSP27 and HSP70 levels and metabolite levels in patients with AF patients (n = 21). Hereto, HSP27 and HSP70 levels were determined by ELISAs and metabolites with LC-mass spectrometry. HSP27 levels significantly decreased after 3-months of L-glutamine supplementation [540.39 (250.97–1315.63) to 380.69 (185.68–915.03), p = 0.004] and normalized to baseline levels after 6-months of L-glutamine supplementation [634.96 (139.57–3103.61), p < 0.001]. For HSP70, levels decreased after 3-months of L-glutamine supplementation [548.86 (31.50–1564.51) to 353.65 (110.58–752.50), p = 0.045] and remained low after 6-months of L-glutamine supplementation [309.30 (118.29–1744.19), p = 0.517]. Patients with high HSP27 levels at baseline showed normalization of several metabolites related to the carbohydrates, nucleotides, amino acids, vitamins and cofactors metabolic pathways after 3-months L-glutamine supplementation. In conclusion, L-glutamine supplementation reduces the serum levels of HSP27 and HSP70 within 3-months and normalizes metabolite levels. This knowledge may fuel future clinical studies on L-glutamine to improve cardioprotective effects that may attenuate AF episodes.

scholarly journals Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

2019 ◽  
Vol 20 (18) ◽  
pp. 4507 ◽  
Author(s):  
Lang ◽  
Guerrero-Giménez ◽  
Prince ◽  
Ackerman ◽  
Bonorino ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Stress Proteins ◽  
De Novo ◽  
Human Cancer ◽  
Essential Components ◽  
Wide Range ◽  
Cancer Types ◽  
Shock Proteins

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

scholarly journals Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts

2006 ◽  
Vol 394 (3) ◽  
pp. 635-645 ◽  
Author(s):  
Rory E. Morty ◽  
Patrick Bulau ◽  
Roger Pellé ◽  
Sherwin Wilk ◽  
Koji Abe
Keyword(s):  
Trypanosoma Brucei ◽  
Half Life ◽  
Specific Inhibitor ◽  
Parasitic Infections ◽  
Type I ◽  
African Trypanosomiasis ◽  
Thyrotrophin Releasing Hormone ◽  
African Trypanosomes ◽  
Releasing Hormone ◽  
Plasma Half Life

Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a kcat/Km value of 0.5 and 0.1 s−1·μM−1 respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.

Chaperones and protein folding in the archaea

2009 ◽  
Vol 37 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Andrew T. Large ◽  
Martin D. Goldberg ◽  
Peter A. Lund
Keyword(s):  
Protein Folding ◽  
Heat Shock ◽  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Heat Shock Protein ◽  
Haloferax Volcanii ◽  
Functional Specialization ◽  
Type I ◽  
Type Ii ◽  
Shock Proteins

A survey of archaeal genomes for the presence of homologues of bacterial and eukaryotic chaperones reveals several interesting features. All archaea contain chaperonins, also known as Hsp60s (where Hsp is heat-shock protein). These are more similar to the type II chaperonins found in the eukaryotic cytosol than to the type I chaperonins found in bacteria, mitochondria and chloroplasts, although some archaea also contain type I chaperonin homologues, presumably acquired by horizontal gene transfer. Most archaea contain several genes for these proteins. Our studies on the type II chaperonins of the genetically tractable archaeon Haloferax volcanii have shown that only one of the three genes has to be present for the organisms to grow, but that there is some evidence for functional specialization between the different chaperonin proteins. All archaea also possess genes for prefoldin proteins and for small heat-shock proteins, but they generally lack genes for Hsp90 and Hsp100 homologues. Genes for Hsp70 (DnaK) and Hsp40 (DnaJ) homologues are only found in a subset of archaea. Thus chaperone-assisted protein folding in archaea is likely to display some unique features when compared with that in eukaryotes and bacteria, and there may be important differences in the process between euryarchaea and crenarchaea.

scholarly journals Mitochondrial Heat Shock Protein Machinery Hsp70/Hsp40 Is Indispensable for Proper Mitochondrial DNA Maintenance and Replication

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Jiří Týč ◽  
Michele M. Klingbeil ◽  
Julius Lukeš
Keyword(s):  
Mitochondrial Dna ◽  
Heat Shock ◽  
Protein Import ◽  
Content Type ◽  
Copy Numbers ◽  
Wide Range ◽  
Shock Proteins ◽  
Mitochondrial Heat Shock Protein ◽  
Mitochondrial Chaperones ◽  
Dna Maintenance

ABSTRACT  Mitochondrial chaperones have multiple functions that are essential for proper functioning of mitochondria. In the human-pathogenic protist Trypanosoma brucei, we demonstrate a novel function of the highly conserved machinery composed of mitochondrial heat shock proteins 70 and 40 (mtHsp70/mtHsp40) and the ATP exchange factor Mge1. The mitochondrial DNA of T. brucei, also known as kinetoplast DNA (kDNA), is represented by a single catenated network composed of thousands of minicircles and dozens of maxicircles packed into an electron-dense kDNA disk. The chaperones mtHsp70 and mtHsp40 and their cofactor Mge1 are uniformly distributed throughout the single mitochondrial network and are all essential for the parasite. Following RNA interference (RNAi)-mediated depletion of each of these proteins, the kDNA network shrinks and eventually disappears. Ultrastructural analysis of cells depleted for mtHsp70 or mtHsp40 revealed that the otherwise compact kDNA network becomes severely compromised, a consequence of decreased maxicircle and minicircle copy numbers. Moreover, we show that the replication of minicircles is impaired, although the lack of these proteins has a bigger impact on the less abundant maxicircles. We provide additional evidence that these chaperones are indispensable for the maintenance and replication of kDNA, in addition to their already known functions in Fe-S cluster synthesis and protein import. IMPORTANCE  Impairment or loss of mitochondrial DNA is associated with mitochondrial dysfunction and a wide range of neural, muscular, and other diseases. We present the first evidence showing that the entire mtHsp70/mtHsp40 machinery plays an important role in mitochondrial DNA replication and maintenance, a function likely retained from prokaryotes. These abundant, ubiquitous, and multifunctional chaperones share phenotypes with enzymes engaged in the initial stages of replication of the mitochondrial DNA in T. brucei.

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