7. Embryol. exp. Morph. 83, Supplement, 147-161 (1984)
Printed in Great Britain © The Company of Biologists Limited 1984
Heat shock — a comparison of Drosophila and yeast
By SUSAN LINDQUIST
The Department of Molecular Genetics and Cell Biology, The University of
Chicago, 1103 E. 57th Street, Chicago, Illinois 60637, U.S.A.
TABLE OF CONTENTS
Introduction
The response to high temperature
Developmental induction
Conclusions
References
INTRODUCTION
When cells or whole organisms are exposed to temperatures slightly above
their optimum for growth, they respond by synthesizing a small group of
proteins, called the heat shock proteins (hsps), which help protect them from the
toxic effects of heat. The same set of proteins can also be induced by a wide
variety of other stresses including exposure to ethanol, heavy metal ions, and
inhibitors of respiratory metabolism. Their induction is apparently a very general
reaction to adverse conditions. (See Schlessinger, Ashburner & Tissieres, 1982,
for review.)
This response is the most highly conserved genetic regulatory system known.
The proteins produced by fruit flies are homologous to those produced by
enterobacteria, corn plants, slime moulds, yeasts, sea urchins, and humans
(Bardwell & Craig, 1984; Key, Lin & Chen, 1981; Loomis & Wheeler, 1980;
McAlister, Strausberg, Kulaga & Finkelstein, 1979; Giudice, Roccheri &
Debernardo, 1980; Thomas, Welch, Matthews & Feramisco, 1982). Related
species have been detected even in archaebacteria (Bardwell & Craig, 1984;
Daniels, McKee & Doolittle, 1984). The list of species in which the heat shock
response has now been studied is enormous.
Determining how this small group of proteins is able to protect such a diverse
spectrum of organisms from so many different types of stress is a fascinating
biological problem. Unfortunately, it is one which still awaits a solution at the
molecular level. But the response has attracted study for another reason as well:
the rapid and extremely reproducible nature of the induction makes it an attractive model system for learning about the mechanisms cells use to alter their
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patterns of gene expression. In this respect investigations have met with great success: heat shock promoter elements have been dissected and used to place other
genes under heat shock regulation (Pelham, 1982; Pelham & Bienz, 1982);
changes in chromatin structure associated with the activation of the genes has
been described in remarkablyfinedetail (Wu, 1980,1984; Keene, Corces, Lo wenhaupt & Elgin, 1983); factors required for preferential transcription have been
fractionated and characterized in vitro (Bonner, 1981; Topol & Parker, 1984).
For the past few years my laboratory has been studying the heat shock responses of two very different organisms - the fruit fly, Drosophila, and yeast,
Saccharomyces cerevisiae. Both organisms are able to achieve a rapid synthesis
of heat shock proteins in response to elevated temperatures. In keeping with the
enormous differences in their biology, however, different regulatory mechanisms are employed to accomplish this induction. Many other basic features of the
response differ in the two organisms. It is somewhat surprising, therefore, that
in both organisms a particular subset of the heat shock proteins is induced during
the normal course of development, in the absence of heat. The similarity between the two developmental inductions indicates it is a very ancient pattern and
suggests that the heat shock proteins not only provide protection from stress but
may also serve an important role in the natural life cycles of many organisms.
THE RESPONSE TO HIGH TEMPERATURE
Both yeast and Drosophila grow well at 25 °C, the temperature normally used
for their culture in the laboratory. In Drosophila, the optimal temperature for
induction of heat shock proteins is between 36 and 37°C (Lindquist, 1980a,b)\
in Saccharomyces cerevisiae, it is between 39 and 40 °C (Lindquist et al. 1982).
Fig. 1 compares the patterns of protein synthesis in these organisms at their
standard growing temperatures and during heat shock.
In both cases, transfer to high temperature is accompanied by a rapid induction of heat shock proteins. In Drosophila the major proteins have relative
molecular masses (Mr) of 83000, 70000, 68000, 28000, 26000, 23000, and
22 000 (designated hsp83, hsp70, etc. for obvious reasons). Yeast has proteins of
84000, 70000, 69000, and 26000, which appear to be analogous to the correspondingly sized proteins of Drosophila. Nucleotide sequence analysis of the
70 000 Mx protein coding genes of the two species predicts 72 % homology at the
amino acid level (Ingolia, Slater & Craig, 1982). Sequence analysis for the other
yeast proteins is not yet complete, but the genes have all been cloned and comparative data should be available soon. A difference between the two organisms
is that yeast cells produce only one small heat shock protein while Drosophila
cells produce four closely related species. An additional difference is that yeast
cells synthesize a protein of 96 000 Mr which does not appear to have a counterpart in Drosophila. In this regard Drosophila is unusual, as most organisms
synthesize a high relative molecular mass species.
Heat shock - a comparison of Drosophila and yeast
Drosophila
Yeast
C HS
C HS
149
^-96
84
_ -70
-26
-28
-26
-23
-22
Fig. 1. Heat shock proteins in Drosophila and yeast. Cells were grown at 25 °C to
mid-log phase and then either maintained at this temperature (C) or heat shocked
for 1 h (HS). 3H-labelled isoleucine was added during thefinal30 min of incubation.
Drosophila cells (Schneider's line No. 2) were heat shocked at 36-5 °C and the
proteins were analysed in 10 % SDS polyacrylamide gels. Yeast cells (strain A364a)
were heat shocked at 39°C and the proteins analysed on 12 % gels. Mt x 10~3.
A major distinction between the Drosophila and yeast responses is in the effect
heat treatment has on normal protein synthesis. As shown in Fig. 1, the
Drosophila response is much cleaner than the yeast response. Normal protein
synthesis is virtually undetectable in Drosophila cells, while in yeast cells it is
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S. LINDQUIST
only partially reduced. A time course of the induction in the two organisms is
more revealing. As shown in Fig. 2, at the maximal induction temperaturejbr
hsp70, 37 °C, the repression of normal protein synthesis in Drosophila cells is
sudden and absolute. Even at more moderate temperatures, where normal
protein synthesis is only partially repressed, the repression is rapidly achieved
and maintained at a constant level. In yeast cells, by contrast, even at high
temperatures the repression is progressive and relatively slow.
The underlying cause of this difference is now known to be a difference in
regulation. In both organisms, the exposure to high temperature results in immediate transcriptional activation of the heat shock genes. Only in Drosophila,
however, is this accompanied by the induction of a specific translational control
mechanism which rigorously discriminates against pre-existing messages.
The evidence for a specific translational mechanism operating in Drosophila
cells is very strong. First, the disappearance of normal cellular protein synthesis
during heat shock is not due to the degradation of pre-existing messages. If heat
shocked cells are treated with actinomycin D (to prevent the synthesis of new
messenger RNAs) and then returned to normal temperatures, the full spectrum
of normal protein synthesis is still restored (McKenzie, 1977; Storti, Scott, Rich
& Pardue, 1980; Lindquist, 1981). That the pre-existing messages have not
•37°C
n
IS
it*
Hi
|PH
1
Drosophila
mm *•* mm mm mm mm *— « • • " •
^m ^ ^ ^ ^ ^ ^ ^ ^ u M g B
mmmt
i im mmmmi^b ^
a a a >
Yeast
Fig. 2. Heat shock time course in Drosophila and yeast. Small aliquots of cells grown
at 25 °C were heat shocked by immersing tubes in water baths at the indicated
temperatures. Every 15 min an aliquot was labelled with [3H]isoleucine. Drosophila
cells were grown and labelled in Shields and Sang medium; yeast cells were grown
in a synthetic acetate medium.
»••
^mmm
Heat shock - a comparison of Drosophila and yeast
151
changed appreciably in concentration or undergone any major physical modifications has been demonstrated by in vitro translation of total cellular RNAs in
cell-free lysates and by hybridization of electrophoretically separated RNAs to
cloned probes (Mirault etal. 1978; DiDomenico, Bugaisky & Lindquist, 1982a).
Second, the messages for normal cellular proteins are not simply swamped out
of translation by the massive influx of new heat shock mRNAs. Within 10 min of
temperature elevation, pre-existing polysomes have all but disappeared. New
polysomes translating the heat shock mRNAs do not appear in substantial numbers for another 10 or 15 min (see Fig. 3). Furthermore, if heat shock message
synthesis is blocked by the addition of actinomycin D before heat shock, preexisting polysomes still disappear.
Third, the change in translational specificity is not simply due to a direct effect
of temperature on the secondary structure of the messenger RNA. Cell-free
lysates made from heat shocked Drosophila tissue culture cells retain the capacity to discriminate against normal cellular messenger RNAs (Storti et al. 1980;
Scott & Pardue, 1981). Lysates made from control cells incubated under the
same conditions show no discrimination. When heat shock messages are mixed
with messages for normal cellular proteins and translated in vitro at various
temperatures, the relative translational efficiency of the two classes is not effected. Finally, when tissue culture cells are heat shocked and returned to 25 °C,
normal patterns of protein synthesis are not restored until a specific quantity of
heat shock protein has been produced, indicating the discrimination against
normal cellular messengers occurs in response to a physiological need for heat
shock proteins and not as a consequence of the temperature shift per se
(DiDomenico et al. 19826).
A change in the pattern of protein synthesis can be produced by a non-specific
decrease in the efficiency of ribosome initiation since different messages naturally have different intrinsic affinities for ribosomes (Lodish, 1976). If heat shock
caused a drastic decline in the overall rate of initiation, heat shock messenger
RNAs might be preferentially translated by virtue of out-competing normal
cellular messages for the limiting initiations. This possibility was eliminated by
measuring the actual rates of ribosome initiation in heat shocked cells. The rates
were found to compare favourably with those of rabbit reticulocytes, one of the
highest known initiation rates in a eucaryotic cell (Lindquist, 19806). The change
in protein synthesis which occurs in Drosophila cells immediately after heat
shock involves a highly specific system of translational control which strongly
inhibits the translation of pre-existing messenger RNAs and promotes the rapid
and efficient translation of heat shock messages.
Yeast cells have no comparable translational mechanism. The gradual decline
in normal cellular protein synthesis during heat shock parallels a gradual
depletion of normal cellular messages from the cell. RNAs isolated at various
times after a shift to 39 °C were analysed by in vitro translation and Northern blot
hybridization. In contrast with results from Drosophila cells, the patterns of
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in vitro protein synthesis closely matched the in vivo labellings. Hybridization of
individual message species with cloned genomic probes indicated that the decline
in translation was due to the loss of message sequences from the cell. As is
apparent in Fig. 2, each individual messenger RNA appears to have its own rate
of disappearance. The most likely explanation for this effect is a combination of
transcriptional inhibition and varying intrinsic rates of message turnover.
(Messenger RNA half-lives in yeast have previously been shown to vary between
4 and 90min with an average of 20 to 25 min.)
It would certainly be a mistake to assume that temperature has no effect on the
translational efficiency of yeast messenger RNAs. Indeed, McLaughlin and his
colleagues (Plesset, Foy, Chia & McLaughlin, 1983) have shown that preexisting messenger RNAs differ in relative translational efficiencies at low and
high temperatures. It is clear, however, that yeast cells have not evolved the sort
of translational mechanism observed in Drosophila cells in which pre-existing
messages are blocked from translation and preserved for later use. This difference in regulation makes biological sense. In Drosophila cells messenger
RNAs typically have half-lives on the order of 6 to 9 h. Furthermore, in healthy
and rapidly growing cells the majority of ribosomes are already engaged in
protein synthesis. Even with a massive change in transcription, then, it would
take several hours to achieve a high level of heat shock protein synthesis without
a special mechanism to clear out the competition. Yeast cells do not have this
problem. With message half-lives on the order of 20 to 30 min high levels of heat
shock protein synthesis can be achieved by simply allowing pre-existing messages
to decay at their own rates.
Another difference in regulation between Drosophila and yeast cells is in the
level of transcriptional induction. In Drosophila, messenger RNA for hsp70 is
present in extremely low concentrations in normal healthy cells. After one hour
of heat shock, the concentration has increased by approximately three orders of
magnitude, reaching afinalconcentration of several thousand molecules per cell.
(See Fig. 3.) In yeast cells, on the other hand, messenger RNA for hsp70 is
present in substantial quantities at normal temperatures. The increase in concentration with heat shock is less than ten-fold.
The significance of this difference is not yet clear. Both Drosophila and yeast
cells contain a family of proteins which are closely related to hsp70 but constitutively expressed (Ingolia & Craig, 1982). It is likely, although by no means
certain, that these proteins have some overlap in function. If so, the balance of
function between the heat induced proteins and their constitutively synthesized
cognates may be different in yeast and Drosophila, accounting for the different
levels of hsp70 inducibility. An answer to this question must await quantitative
analysis of cognate protein expression and biochemical or genetic characterization of function.
In Fig. 4, yet another important difference between yeast and Drosophila is
illustrated. Yeast cells growing by fermentative metabolism have the capacity to
Heat shock - a comparison of Drosophila and yeast
25 °C
30min37°C
10min37°C
+ act. T = 0
5min37°C
153
10min37°C
60min37°C
60min37°C
+ act 0 T = 40
Fig. 3. Effect of heat shock on polysome profiles. Small flasks of tissue culture cells
were submerged in a 37 °C water bath for the indicated times. Actinomycin was
added (1 /ig/ml) before heat shock (F and G) or after 60min. Cytoplasmic lysates
were analysed on 0-5 to l-5M-sucrose gradients.
return to normal patterns of protein synthesis when maintained at high temperature. Yeast cells are able to grow by both fermentation and respiration,
depending upon the carbon source available. In acetate medium they grow
perforce by respiration, but when supplied with dextrose, they prefer to ferment.
Under standard laboratory culture conditions, and presumably during commercial fermentation, the yeast heat shock response is transient, and cells will
resume growth at temperatures as high as 39-40 °C. Drosophila cells and yeast
cells growing by respiratory metabolism do not have this capacity.
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S. LINDQUIST
Fermentative growth
Fig. 4. Transient heat shock in yeast cells. Small aliquots of yeast cells grown to midlog phase at 25 °C in dextrose medium were immersed in a 39 °C water bath and
labelled with [3H]leucine every 20min.
The basis of the ability to recover is not known. Fermentative metabolism is
not the whole story, since yeast cells deficient in mitochondrial metabolism are
also unable to resume growth at normal temperatures, even when growing by
dextrose fermentation. At any rate, transient heat shock, followed by adaptation
to high temperatures, is a property of many other organisms besides yeast. It
seems likely that in some organisms, the heat shock proteins may be involved in
Heat shock - a comparison of Drosophila and yeast
155
adjusting cellular physiology to life at high temperature as well as in protecting
organisms from short-term exposure to extremes.
DEVELOPMENTAL
INDUCTION
It has recently been determined that certain of the Drosophila heat shock
genes are induced during the normal course of development, in the absence of
heat. The expression is both tissue and stage specific. Two stages in the lifecycle
are involved, puparium formation and oogenesis.
During puparium formation, in both sexes, transcripts for all four of the small
heat shock proteins, hsp22, 23, 26, and 28 are produced (Sirotkin & Davidson,
1982). At least one of these, hsp23, is translated into protein (Cheney & Shearn,
1983). The RNAs are observed in imaginal wing discs but not in salivary glands
or in fat bodies. The messages first appear in late third instar larvae, shortly after
release of the moulting hormone ecdysone and disappear from late pupae.
Heat shock genes are not expressed in earlier larval stages nor in adult males.
In adult females, however, messenger RNAs for hsp28, hsp26 and hsp83 are
abundantly transcribed in ovarian nurse cells (Zimmerman, Petri & Meselson,
1983). Transcripts are undetectable in stage-1 to -7 egg chambers, increase
thereafter to reach a maximum at stage 10 and are then passed into the developing oocyte. They remain abundant during the first 3h of embryogenesis and
disappear with formation of the cellular blastoderm.
A distinctive feature of these developmental inductions is that hsp70 is not
induced. In fact, in developing oocytes, hsp70 cannot be induced even with a heat
treatment (Zimmerman et al. 1983). In all other cells and tissues this protein is
the most abundantly synthesized species during heat shock. Its presence seems
to be a very sensitive indicator of stress, since it is produced in tissue culture cells
growing in anything less than ideal conditions (Velazquez, Sonoda, Bugaisky &
Lindquist, 1983). Thus, the developmental induction is very different from a
typical stress response. While hsp70 itself is not developmentally induced, one
of its relatives, the 72000 Mr cognate, is strongly induced in developing oocytes
(Craig & Palter, personal communication).
The signal for the developmental induction appears to be release of the moulting hormone ecdysone. Imaginal wing discs and tissue culture cells treated with
ecdysone in vitro display up to a 15-fold increase in messenger RN A for the small
heat shock proteins (Ireland & Berger, 1982). The induction follows a typical
physiological dosage-response curve, with half-maximal induction at 10~ 8 M.
Ecdysone causes profound changes in cell growth and morphology as well. Notably, cell lines isolated on the basis of resistance to these effects of the hormone
also do not display the hormonal induction of the small hsps (Berger, Vitek &
Morgenelli, 1984).
In investigating the induction of heat shock proteins during development in
yeast, vegetatively growing cells were transferred into sporulation medium and
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RNAs were extracted every few hours. Each sample was analysed for heat shock
messenger RNAs by in vitro translation and Northern blot hybridization.
We were surprised to find that the yeast heat shock proteins showed the same
uncoupled pattern of expression in development as observed in Drosophila.
Messenger RNAs for hsp26 and hsp83 are strongly induced; messenger RNA for
hsp70 is not. Fig. 5 displays the patterns of hybridization obtained when RNAs
isolated at various times during sporulation are electrophoretically separated,
transferred to nitrocellulose, and hybridized with radioactively labelled clone
probes for the heat shock genes. In vitro translation of the same RNAs results
in strong synthesis of hsp26 and hsp83 but not of hsp70. Although we can't be
certain that hsp83 messenger RNA is translated in vivo, experiments with
antibodies against hsp26 demonstrate that the protein is abundant within 6h.
25 27
29
31 33 35
Drosophila
37
25
39
Yeast
Fig. 5. Induction of hsp70 messenger RNA with heat shock. Drosophila and yeast
cells grown at 25 °C to mid-log phase were heat shocked for 1 h at the indicated
temperatures. Total cellular RNAs were extracted, separated on CH3-Hg agarose
gels, transferred to nitrocellulose, and hybridized with a nick-translated plasmid
containing the Drosophila or yeast hsp70 gene.
Heat shock - a comparison of Drosophila and yeast
157
Experiments with another antibody, which recognizes the entire hsp70 and cognate family, extends the analogy with the Drosophila oocyte induction still
further. Although hsp70 itself is not induced in developing spores at normal
V 2
8
12
24h
26
84
70
Fig. 6. Developmental induction of hsp mRNAs during yeast sporulation. Total
cellular RNAs were extracted from yeast cells during vegetative growth and 2, 4, 8,
and 24 h after transfer to sporulation medium. The RNAs were analysed as for Fig.
5 except that in addition to the gene for hsp70, they were also hybridized with the
genes for yeast hsp26 and hsp83.
EMB 83S
158
S. LINDQUIST
temperatures, the 72000 cognate gene is induced (Kurtz, Rossi & Lindquist,
manuscript in preparation).
We do not yet know what the role of the heat shock proteins is in development.
Yeast spores, of course, are characterized by high tolerance to heat. The early
Drosophila embryo, however, is the most heat-sensitive stage in the life cycle
(Graziosi etal. 1980), indicating that in this case, at least, the proteins are serving
some function specific to development. The recent finding that hsp26 is an RNAbinding protein, taken together with the fact that both Drosophila embryos and
yeast spores store large quantities of maternal message, leads to the conjecture
that this protein may be involved in message storage. We have recently created
disruption mutants of hsp26 in yeast which will allow us to test this hypothesis.
An equally interesting question is why, of all the heat shock proteins, hsp70
is specifically excluded from developmental induction. Here, too, the answer
may lie in its distinctive nucleic-acid-binding properties. We have found that the
protein is a single-stranded nucleic-acid-binding protein which concentrates in
nuclei and binds to chromosomes in a specific way (Velazquez, DiDomenico &
Lindquist, 1980; Velazquez & Lindquist, 1984). It may be that the presence of
the protein in meiotic cells would poison some normal nuclear process, such as
DNA replication or recombination. This might explain why hsp70 is quantitatively removed from nuclei during recovery from a standard heat shock.
Placing the hsp70 coding sequence under control of the hsp26 promoter, to
activate it during sporulation, should provide an answer to this question.
CONCLUSIONS
Over the past several years the heat shock response has been the subject of
intense investigation. The speed of the induction, the intensity of the response,
and the reproducibility of the effect have combined to make it an excellent model
system for studying gene expression in an amazing variety of different organisms.
One lesson that has been learned is that different cells and organisms use
different means to achieve the same ends. The point has been illustrated here
with respect to heat shock protein production in Drosophila and yeast. Another
interesting example was provided by Bienz & Gurdon (1982) in studies of
Xenopus. In somatic cells heat shock induction is regulated by a combination of
transcriptional and translational control, much as it is in Drosophila cells. In
oocytes, however, the responses is regulated entirely at the level of translation.
Heat shock messenger RNAs are already present in Xenopus oocytes but they
are not translated efficiently unless the cells are exposed to heat. This again
makes perfect biological sense. The oocyte is so large that, if it had to depend
upon new transcription from a single haploid genome, it would take an inordinate amount of time to mount an effective response.
Another outcome of these comparative studies is the discovery of amazingly
similar developmental patterns of heat shock gene expression in Drosophila
Heat shock - a comparison 0/Drosophila and yeast
159
oogenesis and yeast sporulation. Thefindinghas several interesting implications.
First, it underscores the fundamental biological similarity of the two processes
in these vastly different organisms. Second, it suggests that the developmental
induction of these proteins may be as ancient a phenomenon as the heat induction; their roles in development may be as important, on an evolutionary scale,
as their roles in thermotolerance. Third, the fact that in both organisms the
synthesis of hsp70 has been uncoupled from the other heat shock proteins indicates that there has been a strong selection to evolve independent regulatory
elements. It may be that hsp70 is toxic to some fundamental meiotic process.
Our two major goals in studying the heat shock response are to discover how
these proteins confer protection from the toxic effects of stress and to exploit
their induction as a model system for investigating mechanisms of gene regulation. Both yeast and Drosophila have unique advantages for these studies. Yeast
offers haploid and diploid genetics as well as the powerful advantage of
homologous transformation. Drosophila offers a richer and more complex pattern of differentiation and development together with the extraordinary cytology
of polytene tissues. The benefits of studying these organisms individually are
enhanced by their comparison. The ways in which the responses differ illustrate
the principles by which regulatory mechanisms are honed to particular biological
constraints. The ways in which they are similar provide perspective on the function and evolution of the response.
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