Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

Pockley, A. Graham

doi:10.1017/s1462399401003556

Cited by 85 publications

(76 citation statements)

References 151 publications

(31 reference statements)

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“…We also observed that HSPs were modulated during infection, which may be linked to an increase in transcription and translation, since HSPs are important in protein processing (30). HSPs are present in all cells under normal conditions and during stress (e.g., heat/cold/ oxygen deprivation) and can make up to 15% of the total cellular protein content (68). HSPs ensure the correct conformation of proteins and facilitate the degradation of selected proteins by the ubiquitin/proteasome system, as well as their own inherent activities (30).…”

Section: Vol 76 2008 Modulation Of the Host Cell Proteome By T Gonmentioning

confidence: 70%

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

et al. 2008

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To investigate how intracellular parasites manipulate their host cell environment at the molecular level, we undertook a quantitative proteomic study of cells following infection with the apicomplexan parasite Toxoplasma gondii. Using conventional two-dimensional electrophoresis, difference gel electrophoresis (DIGE), and mass spectrometry, we identified host proteins that were consistently modulated in expression following infection. We detected modification of protein expression in key metabolic pathways, including glycolysis, lipid and sterol metabolism, mitosis, apoptosis, and structural-protein expression, suggestive of global reprogramming of cell metabolism by the parasite. Many of the differentially expressed proteins had not been previously implicated in the response to the parasite, while others provide important corroborative protein evidence for previously proposed hypotheses of pathogen-cell interactions. Significantly, over one-third of all modulated proteins were mitochondrial, and this was further investigated by DIGE analysis of a mitochondrion-enriched preparation from infected cells. Comparison of our proteomic data with previous transcriptional studies suggested that a complex relationship exits between transcription and protein expression that may be partly explained by posttranslational modifications of proteins and revealed the importance of investigating protein changes when interpreting transcriptional data. To investigate this further, we used phosphatase treatment and DIGE to demonstrate changes in the phosphorylation states of several key proteins following infection. Overall, our findings indicate that the host cell proteome responds in a dramatic way to T. gondii invasion, in terms of both protein expression changes and protein modifications, and reveal a complex and intimate molecular relationship between host and parasite.The obligate intracellular protozoan Toxoplasma gondii has evolved an intimate relationship with its host that extends to the cellular and molecular levels (82, 83). The absolute requirement for invasion of an appropriate host cell in the replication of the parasite suggests that modification of host functions is central to pathogenesis. Intuitively, this subversion of the cell must be a complex process, since host cells are not inherently programmed to provide an environment conducive to pathogens. Host cells have evolved primary lines of defense as countermeasures to pathogen invasion, establishment, and replication. These include elaborate systems, such as the phagolysosomal fusion, reactive oxygen and nitrogen intermediates, the sequestration of nutrients, and even cell suicide (apoptosis), as defenses to limit pathogen growth. The implementation of these systems and the ability of successful pathogens to mitigate their effects are ultimately mediated by changes in both the levels and activities of key proteins. While some of these changes may be transcriptionally regulated and thus potentially revealed by microarray analysis, the true effectors are proteins,...

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Section: Vol 76 2008 Modulation Of the Host Cell Proteome By T Gonmentioning

confidence: 70%

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

et al. 2008

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“…HSP are normally present in small amounts within the cytoplasm of all cells in all life forms but can also be released into the extracellular environment in the absence of cellular necrosis. 14 The precise mechanisms by which HSP are actively released by viable cells have not yet been elucidated but we propose that exosomes may play a role in releasing HSP from cells. Inside cells, HSP play a role in protein trafficking, whereby they fold other proteins properly, keep them in correct and functional shape, or transport them from one location to another.…”

Section: Discussionmentioning

confidence: 91%

Proteomic Analysis of Exosomes Secreted by Human Mesothelioma Cells

Hegmans¹,

Bard²,

Hemmes³

et al. 2004

The American Journal of Pathology

309

233

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“…Adapted from (64,145). Further information on the nomenclature and individual family members has been published elsewhere (17,18).…”

Section: Protein Refoldingmentioning

confidence: 99%

Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

Pockley

Henderson

2017

Phil. Trans. R. Soc. B

Self Cite

118

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Contribution to a theme issue 'Heat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators' Keywords:Heat shock (stress) proteins, extracellular, immunity Author for correspondence:A. Graham Pockley, PhD e-mail: graham.pockley@ntu.ac.ukHeat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators 2 | P a g e Abstract Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory "danger signals" for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells.The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals / non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining / regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins therefore form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.Heat shock proteins in health and disease: integrating knowledge to better understand the role of heat shock proteins as therapeutic targets and disease modulators 3 | P a g e 1. Background 'Chance favours the prepared mind ' -Louis Pasteur (1822 -1895 The presence of additional new 'puffs' in the polytene chromosomes of cultured Drosophila larva which were induced following their incubation at an inadvertently high temperature and observed by Ferruccio Ritossa (25 th February 1936 -9 th January 2014) in the early 1960s was unexpected and puzzling. He realised the potential importance of this first evidence that stress can influence gene transcription and induce the synthesis of new proteins, yet found it surprisingly difficult to publish this discovery. It was eventually published in Experientia (1, 2).Ritossa's findings were extended and expanded upon during the next decade and by the mid-to-late 1960s it was clear that exposure of cells containing polytene chromosomes to a variety of environmental stressors resulted in the transcription of novel genes and, presumably, in the synthesi...

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Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

Cited by 85 publications

References 151 publications

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

Proteomic Analysis of Exosomes Secreted by Human Mesothelioma Cells

Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

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