Regulation of heat shock protein 70 release in astrocytes: Role of signaling kinases

Abstract

The ability to mount a successful stress response in the face of injury is critical to the long-term viability of individual cells and to the organism in general. The stress response, characterized in part by the upregulation of heat shock proteins, is compromised in several neurodegenerative disorders and in some neuronal populations, including motoneurons (MNs). Because astrocytes have a greater capacity than neurons to survive metabolic stress, and because they are intimately associated with the regulation of neuronal function, it is important to understand their stress response, so that we may to better appreciate the impact of stress on neuronal viability during injury or disease. We show that astrocytes subjected to hyperthermia upregulate Hsp/c70 in addition to intracellular signaling components including activated forms of extracellular-signal-regulated kinase (ERK1/2), Akt, and c-jun N-terminal kinase/stress activated protein kinase (JNK/SAPK). Furthermore, astrocytes release increasing amounts of Hsp/c70 into the extracellular environment following stress, an event that is abrogated when signaling through the ERK1/2 and phosphatidylinositol-3 kinase (PI3K) pathways is compromised and enhanced by inhibition of the JNK pathway. Last, we show that the Hsp/c70 is released from astrocytes in exosomes. Together, these data illustrate the diverse regulation of stress-induced Hsp/c70 release in exosomes, and the way in which the balance of activated signal transduction pathways affects this release. These data highlight how stressful insults can alter the microenvironment of an astrocyte, which may ultimately have implications for the survival of neighboring neurons.

The Impact of Heat Shock Protein 70 Gene Variations on Clinical Presentation and Outcome in Schizophrenic Inpatients

“…Thanks to their role in the viability of cells as a constitutive and induced mechanism facing adverse environmental conditions, and because of playing as cofactors in the antigen presentation mechanism (reviewed in Javid et al [47] ), Hsps represent good candidates in the study of the molecular mechanisms underlying SZ. Consistently, it has recently been reported that Hsp 72 (alias Hsp 70; http://www.genecards.org/ index.shtml) protects against the neuronal hippocampal apoptosis rate in mice exposed to a model of chronic psychological stress [48] , probably also via activation of the astrocytes, which have been demonstrated to enhance the synthesis of Hsp 70 under stress conditions and to release increasing amounts of Hsp 70 into the extracellular environment following stress [49,50] . Furthermore, it has been demonstrated that induced Hsp activity after administration of arimoclomol was associated with a reduced neurodegenerative progression in animal models for amyotrophic lateral sclerosis [51] .…”

Cell Surface Tetraspanin Tspan8 Contributes to Molecular Pathways of Exosome-Induced Endothelial Cell Activation

“…CD71 regulates proliferation and angiogenesis (41). HSPs are constitutively enriched in exosomes (42) and exosomal HSP70 protects neurons from stress damage (43). The minichromosome maintenance complex member MCM7, highly expressed in many malignancies, is at the core of the DNA replication process (44).…”

Exosomes in stroke pathogenesis and therapy

“…Exosomes derived from embryonic chicken astrocytes contain HSP70 (94). Treatment of astrocytes from newborn mice with high KCl concentrations led to release of exosomes enriched with synapsin, a synaptic vesicle-associated protein that enhances neurite growth and neuronal survival (95).…”