Evolution of the cellular stress proteome: from monophyletic origin to ubiquitous function
University of California, Davis, 1 Shields Avenue, Davis, CA 95616, USA
e-mail: dkueltz{at}ucdavis.edu
Accepted 20 June 2003
![]() |
Summary |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: evolution, cellular stress response, DNA damage response, apoptosis, cell cycle checkpoint, molecular chaperone, environmental stress
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The cellular stress response is associated with essential aspects of
protein and DNA processing and stability in all three super-kingdoms, the
archaea (Macario et al.,
1999), the eubacteria (Hecker
and Volker, 2001
) and eukaryotes
(Feder and Hofmann, 1999
;
Pearce and Humphrey, 2001
).
Our current knowledge of the stress proteome, i.e. all the proteins that are
involved in realizing the cellular stress response through induction,
post-translational modification, or proteinprotein/DNA interaction, is
still fragmentary. Nevertheless, we know that common sets of homologous stress
proteins, including molecular chaperones, cell cycle regulators, proteasome
regulators and DNA repair proteins are induced by stress in archaea,
eubacteria and eukaryotes.
Many of these proteins are among the most highly conserved proteins in all organisms (Table 1). In fact, stress response genes of humans account for 67 (18%) of the 368 phylogenetically most highly conserved proteins (Table 1). They are associated with the most basic constitutive functions of all cells, in addition to their roles for stress adaptation (Fig. 1). Because such functions are evolutionarily ancient it is likely that a core stress proteome appeared early in cellular evolution, helping cells to survive stressful fluctuations in the earth's archaic environment. Thus, the very first organisms and cells may have been eury-tolerant, i.e. they probably had high tolerance limits towards environmental change. Other stress proteins could have originated by gain-of-function mutations or adaptive radiation of genes involved in these basic cell functions at various times during the course of evolution (Fig. 2).
|
|
|
Despite their common origin, some stress proteins in contemporary species
are less well conserved than the examples noted in
Table 1. Two obvious reasons
account for such apparent disparity. First, some fairly basic cellular
structures and metabolic processes in bacteria have diverged significantly
from bacteria during evolution and consequently the proteins involved in these
functions have also diverged. Examples include, among other features, the
development of a nucleus, and differences in the organization of the cell
membrane, the nature of signaling systems (e.g. two-component systems
versus Ser-, Thr-, Tyr-phospho-protein systems) and chromatin
organization. Second, genes encoding the stress proteome in steno-tolerant
species adapted to stable environments (organisms with low tolerance limits
towards environmental change) were subject to modification by natural
selection of mutations that decreased their functionality for the stress
response. The apparent lack of an HSP70 gene in some archaea is an extreme
example in this regard (Macario and de
Macario, 1999). At the same time, new contingencies evolving
around modified stress response genes would have favored specialization and
improved organization. This process must have provided a selective advantage
to steno-tolerant organisms by increasing their fitness and competitiveness in
stable environments. For example, in vertebrates (particularly mammals), a
large number of stress response genes have been recruited into signaling
contingencies that are associated with the immune response, to accommodate the
proteomic basis necessary for the ever more complex nature of the immune
system (Moseley, 2000
;
Lutz, 2000
).
Nonetheless, it is well documented that most basic aspects of the cell stress response are conserved in many species and across a wide spectrum of diverse stresses. This high degree of conservation provides the foundation for analyzing the common nature of the cell stress response and for tracing its evolution and molecular design. To undertake such an analysis, the molecular nature of the threat that induces the cell stress response must first be identified.
![]() |
Cellular stress can be defined as the threat of damage to macromolecules |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Its purpose and adaptive significance arises from temporarily increasing
cellular tolerance limits towards such a threat. Because of this universal
property, the cellular stress response consists of adaptations that maximize
the stabilization, protection and repair of macromolecular structure and
function. Such benefit carries the price of transiently decreasing the cells'
capacity for most of its normal functions by draining metabolic energy and
reducing the conformational flexibility of proteins and DNA. Reduced
conformational flexibility decreases the efficacy of enzymes by slowing the
rate at which structural changes occur in the active site during catalysis
(Hochachka and Somero, 2002).
Through similar kinetic effects, conformational flexibility is also
rate-limiting for functions of other macromolecules.
Despite these disadvantages, the cellular stress response shelters the
ultimate cell function during adverse environmental conditions the
survival of healthy cells. The core stress proteome involved in achieving this
task must have evolved in the very first primordial cells because it is
intimately associated not only with the cellular stress response but also with
basic cellular house-keeping functions
(Fig. 1). For instance, HSP70
is involved in such functions as protein maturation in the endoplasmic
reticulum (Hartman and Gething,
1996) and mitochondrial biogenesis
(Voos and Rottgers, 2002
).
Another example is MSH/mutS mismatch repair (MMR) proteins, which are not only
involved in MMR and the repair of other types of DNA damage
(Kolodner and Marsischky,
1999
) but also in constitutive proof-reading activity during DNA
replication (Marti et al.,
2002
).
Interestingly, the molecular mechanism of damage to DNA and proteins may be
mediated in many cases by stress-induced radical formation and changes in
cellular redox state. This has been demonstrated directly for heavy metal
stress (Schutzendubel and Polle,
2002), ionizing radiation
(Wallace, 1998
), chemical
genotoxin stress (Zeiger,
1993
), osmotic stress (Borsani
et al., 2001
; Gueta-Dahan et
al., 1997
), mechanical injury stress
(Hall and Braughler, 1993
) and
pathogen invasion stress (Splettstoesser
and Schuff-Werner, 2002
), in addition to direct oxidative stress.
Thus, critical parts of a universal stress-sensing mechanism may include (1)
macromolecular damage assessment and (2) monitoring of cellular redox state as
a ubiquitous stress indicator.
It needs to be emphasized at this point that environmental stress often also leads to induction of a second set of adaptive responses in addition to the cellular stress response. This second set of responses differs from the cellular stress response in that it is stressor-/environmental factor-specific, has a slower onset, and is directed at re-establishing cellular homeostasis with regard to the particular environmental factor that is perturbed. Such homeostatic adaptations are only practical when healthy cells survive the initial period of stress by means of the cellular stress response.
![]() |
The cellular response to environmental stress is highly conserved |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
These four mechanisms and their transient activation can be regarded as the
cornerstones of the cellular stress response. They consist of: (1) cell cycle
checkpoint control leading to growth arrest cell cycle checkpoints
induced during stress in eukaryotic cells include the G1/S
checkpoint (Bartek and Lukas,
2001), the G2/M checkpoint
(Bulavin et al., 2002
) and
translational control mechanisms (Brostrom
and Brostrom, 1998
); (2) induction of molecular chaperones (HSPs)
and protein stabilizers molecular chaperones are commonly activated
either by induction (Feder and Hofmann,
1999
) or by post-translational modification, e.g. phosphorylation
of HSP28 via the p38 MAP kinase signaling pathway
(Kato et al., 2001
); (3)
activation of mechanisms for nucleic acid and chromatin stabilization and
repair for instance, eukaryotic pathways involved in DNA repair and
chromatin stabilization include the p53 pathway
(Harkin and Hall, 2000
) and
the NF-kappaB pathway (Vermeulen et al.,
2002
); (4) removal of macromolecular debris generated by stress
this aspect of the cellular stress response is exemplified by the
ubiquitin/proteasome pathway (Fuchs et al.,
1998
).
All of these mechanisms seem to be interconnected via a common
stress signaling network, and have the major purpose of maintaining genomic
and macromolecular integrity during stress. This can only be achieved at the
expense of other cell functions, which explains the transient nature of the
cell stress response and the need for re-establishing cellular homeostasis
with regard to the perturbed parameter(s). For instance, hypertonic stress
causes protein instability (Hochachka and
Somero, 2002) and DNA damage
(Kültz and Chakravarty,
2001a
), which rapidly and transiently induce the cellular stress
response, including cell cycle checkpoints leading to growth arrest
(Kültz et al., 1998
),
increased DNA repair (Kültz and
Chakravarty, 2001a
), the ubiquitin/proteasome pathway
(Pan et al., 2002
), molecular
chaperones (Rauchman et al.,
1997
), and in severe cases, programmed cell death
(Michea et al., 2000
). In
addition to the transient cellular stress response, cells activate a second
set of adaptations that are specific for re-establishing homeostasis perturbed
by hypertonic stress. These adaptations are slower, permanent (until
conditions change again), and exemplified by the activation of transporters
and enzymes that catalyze the accumulation of compatible organic osmolytes
(Hochachka and Somero, 2002
).
From an evolutionary point of view, the cellular stress response represents a
great example for the inherent flexibility and robustness of cellular
organization. It renders cells transiently more tolerant towards temporary
damage-inflicting environmental extremes and allows for slower,
stressor-specific adaptations to materialise.
In multicellular eukaryotes programmed cell death (often called apoptosis) represents an additional common stress response when the dose of stress exceeds the cell's capacity for maintaining genomic and macromolecular integrity. This process serves to avoid tumorigenesis and genetic instability of organisms. Hence, cells have the ability to monitor the severity/degree of stress or stress-induced damage. The monitoring systems must be integral parts of the cellular stress response and are likely to be composed of proteins that function in constitutive DNA repair and protein degradation pathways, as well as cellular redox regulation. Many genes involved in the cellular stress response have been identified, but immense gaps remain to be addressed with regard to their exact functions and interaction with other components of stress pathways.
![]() |
Future directions and evolutionary perspectives on the cellular stress response |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An interesting question from an evolutionary perspective pertains to the above-mentioned hypothesis that primordial cells and organisms were originally eury-tolerant. This hypothesis can be tested by comparing the degree of sequence conservation of key stress response genes in eury-tolerant versus steno-tolerant species. For many species high tolerance limits towards fluctuations in a particular environmental factor are indicative of high tolerance limits towards changes in other environmental factors as well. Thus, if ancestral cells were eury-tolerant (stress tolerant) we would expect key stress response genes to be more highly conserved in contemporary eury-tolerant species than in steno-tolerant species, in which these genes have been evolutionarily optimized for other functions (see above). More comparative data are needed to address this hypothesis.
A complicating factor in such a conceptual framework is the possibility
that some species have secondarily acquired or `reinvented' eury-tolerance,
perhaps by recruiting a few novel genes to reconstitute the cellular stress
response network. This might principally be the case for organisms that
consist mainly of cells with low tolerance limits towards stress, but also
contain particular highly specialized tissues capable of withstanding extreme
stress. Renal inner medullary cells of mammals that are able to tolerate many
forms of extreme environmental stress provide a good example
(Woo and Kwon, 2002;
Borkan and Gullans, 2002
),
which also illustrates that in highly organized metazoans, critical parts of
the stress proteome have to be constitutively expressed for cells to be able
to display a high stress tolerance (Santos
et al., 2003
). The low osmotic stress tolerance of most non-renal
mammalian cell types clearly indicates that it is not sufficient to hold a
stress proteome blue-print encoded by the genome.
Further questions arise when analyzing the cellular stress response in the context of organismal plasticity towards environmental change. Does the expression of a highly functional stress proteome confer increased stress tolerance at the cost of decreased fitness in stable environments? The history of life on earth is that of periodic extinctions, e.g. in the Silurian, Permian, and late Jurassic periods, followed by explosive adaptive radiation of surviving species. Mass extinctions are commonly attributed to sudden and severe environmental change. One of the many factors that would favor survival during such stressful periods is a high capacity of eury-tolerant species to tolerate such environmental change. The extraordinary conservation of critical elements of the stress proteome, in combination with other adaptive features in such species, may contribute towards enhancing their potential for surviving catastrophic events such as asteroid impacts. Following mass extinctions, lack of competition probably resulted in promoting rapid adaptive radiation of surviving species into suddenly open ecological niches.
Steno-tolerant species, although more complex and highly organized, are more susceptible to sudden changes in the earth's climate, possibly because critical stress response genes were subject to more extensive modification during evolution to accommodate the higher complexity and organization resulting in increased fitness in stable environments. On a vast time scale one could view the evolutionary process of life on earth as a succession of periods of stability favoring adaptive radiation of steno-tolerant species, interspersed with periods of sudden, severe and global environmental change favoring natural selection of eury-tolerant species. Although many factors are important for surviving mass extinctions, the phenomenon of maintenance and natural selection of eury-tolerance may be one of the critical elements. This phenomenon could be described as Mega-Evolution, and may explain the abundance of eury-tolerant species despite the enormous selection pressure towards ever greater specialization over successive cycles of mass extinctions and adaptive radiations. The underlying evolutionary driving force for such Mega-Evolution merits further study, but it seems plausible that a high capacity for a cellular stress response is one of the crucial pre-requisites for such a process. I hope that this paper helps to invigorate projects tackling the physiological and evolutionary significance of the cellular stress response.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bartek, J. and Lukas, J. (2001). Pathways governing G1/S transition and their response to DNA damage. FEBS Lett. 490,117 -122.[CrossRef][Medline]
Borkan, S. C. and Gullans, S. R. (2002). Molecular chaperones in the kidney. Annu. Rev. Physiol. 64,503 -527.[CrossRef][Medline]
Borsani, O., Valpuesta, V. and Botella, M. A.
(2001). Evidence for a role of salicylic acid in the oxidative
damage generated by NaCl and osmotic stress in Arabidopsis seedlings.
Plant Physiol. 126,1024
-1030.
Brostrom, C. O. and Brostrom, M. A. (1998). Regulation of translational initiation during cellular responses to stress. Prog. Nucleic Acid Res. Mol. Biol. 58, 79-125.[Medline]
Bulavin, D. V., Amundson, S. A. and Fornace, A. J. (2002). p38 and Chk1 kinases: different conductors for the G(2)/M checkpoint symphony. Curr. Opin. Genet. Dev. 12,92 -97.[CrossRef][Medline]
Farrer, B. T. and Pecoraro, V. L. (2002). Heavy-metal complexation by de novo peptide design. Curr. Opin. Drug Discov. Dev. 5,937 -943.[Medline]
Feder, M. E. and Hofmann, G. E. (1999). Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu. Rev. Physiol. 61,243 -282.[CrossRef][Medline]
Fuchs, S. Y., Fried, V. A. and Ronai, Z. (1998). Stress-activated kinases regulate protein stability. Oncogene 17,1483 -1490.[CrossRef][Medline]
Galloway, S. M., Deasy, D. A., Bean, C. L., Kraynak, A. R., Armstrong, M. J. and Bradley, M. (1987). Effects of high osmotic strength on chromosome aberrations, sister-chromatid exchanges and DNA strand breaks, and the relation to toxicity. Mutat. Res. 189,15 -25.[CrossRef][Medline]
Gueta-Dahan, Y., Yaniv, Z., Zilinskas, B. A. and Ben Hayyim, G. (1997). Salt and oxidative stress: similar and specific responses and their relation to salt tolerance in citrus. Planta 203,460 -469.[CrossRef][Medline]
Hall, E. D. and Braughler, J. M. (1993). Free radicals in CNS injury. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 71,81 -105.[Medline]
Harkin, D. P. and Hall, P. A. (2000). Measuring a cell's response to stress: the p53 pathway. Genome Biol. 1,R105 .
Hartman, D. and Gething, M. J. (1996). Normal protein folding machinery. Experientia Suppl. 77, 3-24.
Hecker, M. and Volker, U. (2001). General stress response of Bacillus subtilis and other bacteria. Adv. Microb. Physiol. 44, 35-91.[Medline]
Hochachka, P. W. and Somero, G. N. (2002).Biochemical Adaptation: Mechanism and Process in Physiological Evolution. 3rd edition . Oxford: Oxford University Press.
Kasprzak, K. S. (2002). Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Radic. Biol. Med. 32,958 -967.[CrossRef][Medline]
Kato, K., Ito, H., Iwamoto, I., Lida, K. and Inaguma, Y. (2001). Protein kinase inhibitors can suppress stress-induced dissociation of Hsp27. Cell Stress. Chaper. 6, 16-20.[Medline]
Kempner, E. S. (1993). Damage to proteins due to the direct action of ionizing radiation. Q. Rev. Biophys. 26,27 -48.[Medline]
Kolodner, R. D. and Marsischky, G. T. (1999). Eukaryotic DNA mismatch repair. Curr. Opin. Genet. Dev. 9,89 -96.[CrossRef][Medline]
Kültz, D. and Chakravarty, D. (2001a).
Hyperosmolality in the form of elevated NaCl but not urea causes DNA damage in
murine kidney cells. Proc. Natl. Acad. Sci. USA
98,1999
-2004.
Kültz, D. and Chakravarty, D. (2001b). Maintenance of genomic integrity in mammalian kidney cells exposed to hyperosmotic stress. Comp. Biochem. Physiol. 130A,421 -428.
Kültz, D., Madhany, S. and Burg, M. B.
(1998). Hyperosmolality causes growth arrest of murine kidney
cells. Induction of GADD45 and GADD153 by osmosensing via stress-activated
protein kinase 2. J. Biol. Chem.
273,13645
-13651.
Liu, P. K. (2001). DNA damage and repair in the brain after cerebral ischemia. Curr. Top. Med. Chem. 1, 483-495.[Medline]
Lutz, W. (2000). Metallothioneins as stressor proteins modulating the immune response. Med. Pr. 51,391 -400.[Medline]
Macario, A. J. and de Macario, E. C. (1999).
The archaeal molecular chaperone machine: peculiarities and paradoxes.
Genetics 152,1277
-1283.
Macario, A. J., Lange, M., Ahring, B. K. and de Macario, E.
C. (1999). Stress genes and proteins in the archaea.
Microbiol. Mol. Biol. Rev.
63,923
-967.
Marti, T. M., Kunz, C. and Fleck, O. (2002). DNA mismatch repair and mutation avoidance pathways. J. Cell Physiol. 191,28 -41.[CrossRef][Medline]
Michea, L., Ferguson, D. R., Peters, E. M., Andrews, P. M.,
Kirby, M. R. and Burg, M. B. (2000). Cell cycle delay
and apoptosis are induced by high salt and urea in renal medullary cells.
Am. J. Physiol. Ren. Physiol.
278,F209
-F218.
Moseley, P. L. (2000). Exercise, stress, and the immune conversation. Exerc. Sport Sci. Rev. 28,128 -132.[Medline]
Pan, F., Zarate, J. and Bradley, T. M. (2002).
A homolog of the E3 ubiquitin ligase Rbx1 is induced during hyperosmotic
stress of salmon. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 282,R1643
-R1653.
Pearce, A. K. and Humphrey, T. C. (2001). Integrating stress-response and cell-cycle checkpoint pathways. Trends Cell Biol. 11,426 -433.[CrossRef][Medline]
Rauchman, M. I., Pullman, J. and Gullans, S. R. (1997). Induction of molecular chaperones by hyperosmotic stress in mouse inner medullary collecting duct cells. Am. J. Physiol. 273,F9 -17.[Medline]
Rydberg, B. (2001). Radiation-induced DNA damage and chromatin structure. Acta Oncol. 40,682 -685.[CrossRef][Medline]
Santos, B. C., Pullman, J. M., Chevaile, A., Welch, W. J. and
Gullans, S. R. (2003). Chronic hyperosmolarity mediates
constitutive expression of molecular chaperones and resistance to injury.
Am. J. Physiol. Ren. Physiol.
284,F564
-F574.
Schutzendubel, A. and Polle, A. (2002). Plant
responses to abiotic stresses: heavy metal-induced oxidative stress and
protection by mycorrhization. J. Exp. Bot.
53,1351
-1365.
Somero, G. N. (1992). Adaptations to high hydrostatic pressure. Annu. Rev. Physiol. 54,557 -577.[CrossRef][Medline]
Splettstoesser, W. D. and Schuff-Werner, P. (2002). Oxidative stress in phagocytes `the enemy within'. Microsc. Res. Tech. 57,441 -455.[CrossRef][Medline]
Vermeulen, L., De Wilde, G., Notebaert, S., Vanden Berghe, W. and Haegeman, G. (2002). Regulation of the transcriptional activity of the nuclear factor-kappaB p65 subunit. Biochem. Pharmacol. 64,963 -970.[CrossRef][Medline]
Voos, W. and Rottgers, K. (2002). Molecular chaperones as essential mediators of mitochondrial biogenesis. Biochim. Biophys. Acta 1592,51 -62.[Medline]
Wallace, S. S. (1998). Enzymatic processing of radiation-induced free radical damage in DNA. Radiat. Res. 150,S60 -S79.[Medline]
Woo, S. K. and Kwon, H. M. (2002). Adaptation of kidney medulla to hypertonicity: role of the transcription factor TonEBP. Int. Rev. Cytol. 215,189 -202.[Medline]
Zeiger, E. (1993). Mutagenicity of chemicals added to foods. Mutat. Res. 290, 53-61.[Medline]