Stress: Heat shock proteins

As I do conduct experiments with Heat Shcok Proteins in relation to
the immune system in my lab., here is something to read about how our
cells react towards "Stress" of different forms.

Heat shock proteins (Hsp) play both a protective and a restorative
role in the human body. These molecules are expressed when cells are
stressed by heat, a lack of blood flow, or an influx of heavy metals,
among other circumstances. Because of these outside shocks, some
cellular proteins denature. Heat shock proteins bind to the denatured
proteins, preventing them from forming damaging aggregates. They also
refold other denatured proteins and shepherd them to degradation
pathways within the cell.
Experiments in E. coli, yeast, fruit flies and mice have shown that
increased expression of these proteins can protect the organism
against stress-induced damage.

Despite the obvious importance of stress responses, only recently has
research focused on the role of heat shock proteins in the control of
disease pathology and in the survival and virulence of pathogens.
Knowlege about Hsp functions in bacteria is much further advanced than
in eukaryotes, but already some hints of Hsp involvement in mammalian
diseases have emerged. Here is a list of phenomena.

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Viral infection induces Hsp expression. Bacterial viruses use Hsps to
facilitate takover of the cellular DNA replication machinery, and they
employ Hsps for assembly of virus particles. In eukaryotes, heat shock
proteins associate with key viral products, such as simian virus 40
(SV40) T-antigen, that control cell cycle progression and cause tissue
transformation (cancer).

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Oxidative stress induces Hsp expression. Immune cells release nitric
oxide and superoxide in the attack on invading cells. Host cells
express Hsps to protect against oxidative damage. Unfortunately, the
pathogens also mount a protective response with massive overproduction
of Hsps.

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Hsp70 conveys peptide antigens for presentation to the immune system.
Similar to its role in delivery of newly-synthesized proteins to the
mitochondrion and ER, Hsp70 delivers peptides to the endoplasmic
reticulum and proteins to the lysosome. Peptides generated by the
proteasome in the cytoplasm are transported through the ER membrane
via TAP transporters, loaded into class I major histocompatibility
(MHC) proteins, and presented to CD8 cytotoxic T-cells. Peptides
generated by acid hydrolases in the lysosomes are loaded into class II
MHC proteins and presented to CD4 helper T-cells.

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Hsps are immunodominant antigens. Since they are so abundantly
expressed, Hsps swamp the immune system with epitopes. Despite that
they are highly conserved proteins, sufficient sequence divergence
allows the mammalian immune system to avoid tolerance of Hsps. In some
cases, anti-Hsp responses are protective. In other cases, anti-Hsp
responses are thought to initiate or propagate autoimmune disease by
cross-reacting with self Hsps. In still other cases, a response
against self Hsp (Hsp60) paradoxically suppresses autoimmune disease
symptoms!
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Emotional as well as mechanical stresses induce Hsp expression. When
rats are physically restrained, their vascular endothelial cells
express elevated levels of Hsp70. The response has been linked to an
abrupt increase in blood pressure.

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Elevated Hsp70 expression protects against cardiac failure. Hearts of
transgenic mice that express elevated Hsp70 sustain less damage as a
result of an experimental ischemic event.

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Hsp100 is necessary for propagation of prions in yeast. Aggregates of
the Sup35 protein propagate themselves in a reaction that depends on
yeast Hsp100. Although mammalian prions are composed of an unrelated
protein, experiments with transgenic mice suggest that the species
barrier is at least partly imposed by interactions between the prion
proteins and a host factor that could be a molecular chaperone.

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Neurons are acutely sensitive to stress, possibly because they exhibit
little or no stress response. In contrast, glia and other non-neuronal
cells exhibit a robust stress response. Some evidence indicates that a
specific mechanism transports Hsps from support cells to neurons
during stress.

Essam Refai Med.Lic.
Karolinska Institutet
MBB, Chemistry I
S-171 77 STOCKHOLM
SWEDEN