IOP Genomics - October 2008 - number 3
IOP: Cellular protein defence
Improving the cellular defence
system by enhancing stress response
Stress conditions like heat and exposure to toxins cause eukaryotic cells to upregulate a
and Huntington’s disease. But also in chronic
cellular defence and survival system. This so-called stress response system repairs or disposes
inflammatory diseases like rheumatoid arthritis.”
of misfolded proteins. During ageing the system starts to fail, increasing the risk of age-related
Since different factors can induce the stress
protein folding diseases like Alzheimer’s or Huntington’s disease, as well as of chronic
response, researchers have used them to boost
inflammatory disease. In this IOP project the researchers are looking for ways to boost the
up the defence and repair system. For example,
repair and defence system, which may prevent or treat these diseases.
Willem van Eden and his group, also partners in
the IOP project, have found that various forms
of arthritis in rat and mouse models could be
IOP Project
Under normal, non-stressful conditions
suppressed by HSP immunization or by
members of the heat shock protein (HSP) family
boosting the heat shock system. The IOP
are present in all cells in all life forms. They are
participating group of Harrie Kampinga has
also referred to as stress proteins and their
shown that triggering the stress system is
upregulation is sometimes described more
beneficial in animal models for atrial fibrillation
generally as part of the stress response. HSPs
(cardiac arrhythmia). Others have published
act like ‘chaperones’, making sure that the cell’s
similar results for a polyglutamine disease
proteins are in the right shape and in the right
(spinal and bulbar muscular atrophy) and for
place at the right time ­– just as their stress
Amyotrophic Lateral Sclerosis (ALS). A clinical
induced relatives do in the stressed cell.
trial is running now in the USA in which the
They help new or distorted proteins fold into
efficacy of arimoclomol, a co-inducer of the
shape, which is essential for protein function.
stress response, is tested in ALS patients.
They also assist the transport of proteins from
one compartment to another inside the cell, and
Critical nodes
the transfer of irreversibly misfolded proteins to
Lubsen: “With increasing age the transcription
‘garbage disposals’ inside the cell. Furthermore,
factors that regulate the expression of HSPs
Utrecht University; Faculty of Veterinary
HSPs play a role in triggering the immune
become inactive and the system can no longer
Medicine, Utrecht University; Faculty of
system. They help to present pieces of the
be upregulated this way. Furthermore, the
Medical Science, Groningen University;
proteins (peptides) on the cell surface, which
only known way to upregulate the stress
Faculty of Science, Radboud University
helps the immune system to recognize diseased
system is to cause cellular stress, which
Nijmegen.
cells. In this way HSPs induce anti-inflammatory
ultimately may be deleterious. Our aim is to
• Business partners Unilever R&D, Pepscan
immunoregulatory T cell responses, and in
find ways to boost the defence and repair
Presto, Angteq, Galapagos, ModiQuest,
experimental models HSPs have proven to
system without the deleterious effects.
DSM, Alfa Biogene International, Solvay.
prevent or arrest inflammatory damage.
However, to do that we need to know more
“The integrity of the stress response system is
about the system, its critical nodes and rate
crucial for cell survival,” says Lettie Lubsen,
limiting steps.”
professor of Molecular Biology at the Radboud
So far some 60 heat shock proteins have been
University in Nijmegen. She is leader of one the
found. For most of these the precise function
academic teams participating in the IOP project.
is not known. Only a few have been described
“The system ensures the quality control of
more extensively in the scientific literature.
cellular proteins with respect to structure as
“We want to know which proteins are crucial
well as synthesis and degradation. Increasing
elements in the prevention of age-related
failure of the cellular repair and quality control
diseases. Possibly we can upregulate one or
mechanisms is thought to be involved in many
more of these proteins, to prevent or treat
age-related syndromes in which large protein
these diseases. The challenge in upregulation
aggregates are found, for instance Alzheimer’s
is to bypass the stress activated transcription
• Title Helping Health: Boosting the cellular
defence system.
• Participants Faculty of Chemistry,
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IOP Genomics - October 2008 - number 3
factors. In addition, by measuring the level of
role of HSPs in the immune system; Professor
crucial proteins we may have a read-out
Ineke Braakman’s group studies the role of
system for checking the cell’s health. This way
HSPs in the endoplasmatic reticulum (the
one could check if (older) patients are healthy
cellular protein factory); and the teams of
enough to undergo certain treatments.”
Professor Harrie Kampinga and Professor
Since the stress system is active in different
Lettie Lubsen focus on cytoplasmic proteins.
‘young’
‘old’
stress
stress
compartments of the cell and also plays a
systemic role in the immune system, all these
Harvest
different aspects need to be studied in order
“In the first IOP project we discovered some
to be able to manipulate the system. The
essential proteins, which we want to study in
research required a multidisciplinary approach
more detail in our second IOP project,” says
and therefore four different academic groups
Professor Lettie Lubsen. The essential proteins
Figure 2 Heat shock protein pattern in
collaborated in this IOP-project and its
were discovered by using cell-based model
‘young’ and ‘old’ cells before and after
follow-up. The research group of Professor
systems for protein folding diseases in which
stress. Cells contain a lot of chaperone
Willem van Eden specifically focuses on the
the action of single HSP proteins can be
proteins (green) and young cells under
studied. For in vivo studies Drosophila models
non-stress condition also contain
IOP Genomics
Report
for protein folding disease and longevity are
stress-regulated chaperones (orange).
used as well. Mouse models were used to
Under stress conditions, more chaperones
discover crucial proteins for induction of the
are made (red). ‘Old’ cells lack the
immune system. “Fortunately, a new project
stress-regulated chaperones under
has been funded, so hopefully we will now be
non-stress conditions and also cannot
What is going on in the field of
able to reap the harvest from the investments
increase chaperone synthesis when
genomics? Read about it in the three-
we have made in the first project.”
stressed; they only contain the non-stress
monthly newsletter on the progress and
Lubsen is very satisfied with the way the
regulated chaperones (green).
developments in the IOP Genomics
academic groups collaborated. “There are very
Source: Inauguration
programme and the national genomics
open discussions. Next to the regular meetings
Professor Lettie Lubsen (2008)
strategy. For previously published
there was a lot of e-mail contact between the
Genomics Reports in pdf format and
groups, especially between the PhD students,
for a free subscription go to:
and also a lot of research material was
circumventing the route of stress-related
www.senternovem.nl/iopgenomics/
exchanged.”
induction of the transcription factors.
nieuwsbrief.
“In the beginning there was not such an active
At this stage the participating companies
In due time, the IOP Genomics Report
role for the participating companies, but this
can contribute by delivering all kinds of
will switch from paper to a digital
was also due to the very fundamental
compounds that we can test for effectiveness.
publication. If you do not receive the
character of the research at that early stage.
Eventually they might be used in human
digital edition of the IOP Genomics
However, the fundamental stage of finding
medicine or as food components. Initially,
report, and you wish to receive the
essential HSPs is crucial for the success of the
tissue culture cells will be used to test the
intended digital newsletter in the future,
whole project.”
usefulness of such compounds and later on we
please leave your e-mail address in the
“In the second project we want to develop
will use mouse models for human diseases.”
online subscription form.
bioactive compounds that affect the
expression of the essential proteins (targets)
Diagnostic test
“Since some interesting HSP proteins have now
been discovered, we hope to explore whether
Natural
Non-natural
Fever
Hyperthermia
we can use them as targets in antibody-assays,”
says Dr. Jos Raats, Managing Director of
ModiQuest. ModiQuest develops diagnostics
and therapeutics for the human market.
Infection
(hygiene hypothesis)
Figure 1
Natural and non-natural
factors which can induce
Commercial microflora (probiotics?)
HSP-inducing drugs
antibodies for use in diagnostic tests to detect
Conserved HSPderived peptides
and/or proteins
(oral or parenteral
administration)
Source: Nature Reviews
markers for certain diseases. As a company,
we are of course interested in new markers
with predictive and commercial value and
therefore this project is interesting to us. We
the stress response
system.
“We specifically focus on the development of
Mechanical stress
Whole-cell vaccines
(such as pertussis)
contribute to this project by delivering
knowledge and reagents. The ultimate goal is
to develop a diagnostic test that is indicative
Immunology (2005)
for the stress level and stress resistance of cells.”
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