HIGHLIGHTED TOPICS
Molecular Biology of Thermoregulation
Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

	ABSTRACT

TOP ABSTRACT INTRODUCTION CELL DEATH AND SURVIVAL... SIGNALING PATHWAYS REGULATE... HSPS CONTROL APOPTOTIC... OUTLOOK REFERENCES

Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH₂-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.

thermotolerance; heat shock proteins; mitogen-activated protein kinases; apoptosis

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CELL DEATH AND SURVIVAL... SIGNALING PATHWAYS REGULATE... HSPS CONTROL APOPTOTIC... OUTLOOK REFERENCES

EXPOSURE OF MAMMALIAN CELLS to elevated temperatures (heat shock) triggers several signaling pathways, some that facilitate cell survival and some that initiate cell death programs. The outcome of a cell's exposure to heat shock may be either a development of a state of tolerance to heat shock and other stresses, if survival pathways prevail, or cell death, if death pathways prevail. The first-discovered survival pathway activated by heat shock was the heat shock response, i.e., induction of heat shock proteins (HSPs) such as HSP72, HSP27, HSP40, and HSP90, mediated by heat shock transcription factors (HSFs) (see Ref. 46 for a recent review). HSPs confer thermotolerance as well as resistance to other stresses, such as ethanol, heavy metals, oxidative stress, ischemia, or tumor necrosis factor (see Refs. 16 and 23 for review).

Heat shock causes extensive denaturation and aggregation of intracellular proteins; therefore, early studies focused on the search of labile critical proteins whose damage when exposed to heat shock may lead to cell death (see Refs. 25 and 26 for review). Among major proteins easily denatured and aggregated in heat-shocked cells were components of nuclear matrix and cytoskeleton (2, 25, 26, 31, 41), although it should be noted that there are no data directly linking damage of these proteins to cell death. HSPs serve as molecular chaperones in refolding, disaggregation, and degradation of damaged polypeptides (see Refs. 15 and 21 for review). In fact, aggregation of nuclear proteins as well as a reporter enzyme (firefly luciferase) after heat shock was reduced in thermotolerant cells expressing HSPs, and these cells demonstrated faster solubilization of aggregated proteins during the recovery period (2, 26, 42, 53). Furthermore, expression of HSP72 (the major inducible member of the HSP70 family) alone was sufficient to reduce nuclear protein aggregation and accelerate refolding of luciferase after heat shock (42, 54).

Unexpectedly, recent studies indicated that there are other factors, in addition to suppression of protein damage, that significantly contribute to the protective function of HSPs. Although protein damage is detectable even at slightly elevated temperatures (43-45°C) (47), under these conditions heat shock appears to kill cells not by irreversible damage of critical structures of the cell but via activation of a programmed cascade of events leading to cell demise. Remarkably, under these conditions, HSPs can protect cells from heat-induced killing by interfering with the cell death program.

One of two main modes of cell death evoked by nonextreme temperatures is apoptosis. In many cell types, however, moderate heat shock does not cause apoptosis; nevertheless, cells die after several divisions and are unable to form colonies (clonogenic or reproductive cell death). At present, little is known about mechanisms of reproductive cell death. In contrast, during the past decade, great progress has been made in the understanding of apoptosis, and we will mainly focus on regulation of this form of heat-induced programmed cell death in this review. Of note, although reproductive cell death and apoptosis have distinct morphological characteristics and, obviously, different biochemical mechanisms, initial signaling events in these two types of cell death may be similar (see below).

	CELL DEATH AND SURVIVAL PATHWAYS ACTIVATED BY HEAT SHOCK

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In addition to induction of heat shock responses, elevated temperatures can trigger death-signaling pathways via activation of stress kinase c-Jun NH₂-terminal kinase (JNK) (58) and survival pathways via activation of Akt and extracellular signal-regulated kinases (ERK) (35, 61). The extent of activation of these pathways may affect the fate of cells exposed to heat shock. Indeed, inhibition of JNK dramatically suppressed heat-induced apoptosis of lymphoid cells (11, 40, 58) and rat fibroblasts (60), whereas inhibition of Akt or ERK strongly increased apoptosis (35, 61).

How do these pathways modulate apoptotic cell death due to heat shock and other stresses? The key element of the heat-activated apoptotic cascade is efflux from mitochondria of cytochrome c, which activates a cascade of caspases, including caspase-9 and caspase-3 (33, 39, 49), leading to execution of apoptosis (Fig. 1). JNK activation is involved in stress-induced efflux of cytochrome c from mitochondria (56), possibly via cleavage of the proapoptotic protein Bid (Ref. 56 and V. L. Gabai, unpublished observations) or phosphorylation (and inactivation) of the anti-apoptotic proteins Bcl-2 and Bcl-x (28, 52, 64). Another important apoptotic pathway triggered by heat shock involves induction of Fas ligand with subsequent engagement of Fas receptors and the caspase-8/caspase-3 cascade (51) (Fig. 1). Activation of this pathway by heat shock is also likely to involve JNK, since this kinase was shown to be critical for stress-induced expression of Fas ligand (13, 14).

View larger version (33K): [in this window] [in a new window]   Fig. 1.   Activation of cell death and survival pathway by heat shock. Heat shock activates survival (red) and death (blue) pathways that modulate efflux of cytochrome c (cyt c) from mitochondria and engagement of caspase cascade. ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase.

Survival kinases Akt or ERK may interfere with heat-induced apoptosis in several ways. Briefly, activation of Akt was shown to inhibit JNK (possibly through induction of JNK-inhibitory protein-1), to inactivate a proapoptotic protein Bad, and to activate prosurvival transcription factors nuclear factor-B and FKHRL1 (8, 10, 27, 32). ERK can interfere with Fas-induced activation of caspase-8 (57) and cytochrome c-induced activation of caspase-3 (12). However, which of these pathways plays a role in protection from heat-induced apoptosis is yet to be established.

Besides classical caspase-dependent apoptosis, JNK, Akt, and ERK kinases can also regulate caspase-independent death pathways. When exposed to severe heat shock, human fibroblasts underwent a death that was morphologically indistinguishable from apoptosis but independent of caspases. However, these fibroblasts could survive such heat shock if JNK was inhibited (19). On the contrary, if ERK or Akt kinases were inhibited, much milder heat shock, not toxic to control cells, killed almost 100% of the cell population (19) via a caspase-independent apoptosis. Furthermore, heat-induced clonogenic cell death was also reduced when JNK activity was inhibited (66) and increased when the Akt pathway was blocked (35). Although the mechanisms of caspase-independent apoptosis and clonogenic cell death are still obscure, it seems that JNK, Akt, and ERK cascades play major roles in regulation of these modes of death, as with caspase-dependent apoptosis. These data indicate that it was not heat shock-induced protein damage itself but rather activation of a death program (JNK) that evoked cell death, whereas activation of survival pathways (ERK and Akt) interfered with the death program; ultimately, the interplay of these pathways determined cell fate.

	SIGNALING PATHWAYS REGULATE HSPS

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There is an interplay between the heat shock-induced HSPs and the heat shock-activated signaling pathways. The latter can modulate expression and chaperone function of HSPs, whereas HSPs can modulate signaling events. As stated above, the main mechanism of induction of HSPs is through HSF1-mediated activation of transcription of HSPs genes. It is commonly accepted that denatured cell proteins, accumulated as a consequence of heat shock, titrate out HSP70 and HSP90 from the complex with HSF1, thus activating the latter (see Refs. 37 and 46 for review). In addition, activity of HSF1 is regulated by reversible phosphorylation at multiple sites. Many kinases are involved in this regulation, including heat-activated Akt, ERK, and JNK kinases. For example, heat-induced activation of Akt increased HSF1 activity, possibly through inhibition of glycogen synthase kinase-3 (3), a negative regulator of HSF1 (6, 62). On the other hand, heat shock-induced activation of ERK and JNK decreased HSF1 activity through phosphorylation at distinct sites (6, 9, 22). Therefore, it seems that regulation of HSP transcription by stress-activated signaling pathways may be an important factor affecting balance between death and survival programs.

Beside transcriptional regulation of HSF1, heat-activated kinases may be involved in posttranscriptional modulation of chaperone activity and, e.g., in phosphorylation of HSP27. Molecular chaperone HSP27 can be phosphorylated at serine residues by MAPKAP-2/3 kinase, a distal component of the p38 kinase pathway (29, 30). Along with JNK and ERK, p38 kinase is a member of the mitogen-activated protein stress kinase (MAPK) family, which is strongly activated by heat shock and some other stresses (29). It seems that phosphorylation of HSP27 is important for survival of cells after heat shock. Indeed, if overexpression of HSP27 can confer thermoresistance, overexpression of a mutant HSP27 lacking phosphorylation sites did not protect cells from heat shock (30). Therefore, both transcription of HSPs and their activity (i.e., HSP27) appear to be regulated by stress-activated signaling pathways.

	HSPS CONTROL APOPTOTIC SIGNALING PATHWAYS

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HSPs, in their turn, can modulate cell signaling, providing a feedback loop. As mentioned above, both HSP27 and HSP72 can confer protection against heat-induced killing when overexpressed. HSP27 can interfere with an apoptotic signal transduction at several steps. It is implicated in preserving mitochondrial integrity and reducing cytochrome c release (49); it can bind directly to cytochrome c, thus preventing activation of procaspase-9 (4, 7, 20); and it can bind to procaspase-3 and inhibit its activation (7, 44) (Fig. 2). Furthermore, HSP27 can interact with Daxx, a component of Fas-induced apoptotic pathway, and this interaction was shown to be important for protection from apoptosis (5). However, which of these activities of HSP27 are essential for protection against heat shock-induced cell death is yet to be found.

View larger version (44K): [in this window] [in a new window]   Fig. 2.   Suppression of apoptotic pathway by heat shock protein (HSP) HSP27 and HSP72.

Although the protective effect of HSP72 against heat-induced killing was discovered about two decades ago (see Ref. 15 for review), the mechanism of such protection began to emerge only recently. HSP72 may inhibit the apoptotic pathway by preventing activation of caspase-9 via direct binding to Apaf-1 (see Fig. 2) (1, 48). This activity of HSP72, however, has been demonstrated only in vitro, and the physiological significance of this finding is yet to be determined. In tumor cells, HSP72 may inhibit apoptosis acting downstream of caspases (24). Expression of HSP72 dramatically reduces activation of JNK by heat shock (18, 38), and this effect of HSP72 appears to be critical for inhibition of apoptosis in nontransformed cells (18). Beside classical caspase-dependent apoptosis, suppression of JNK by HSP72 also appears to play an important role in caspase-independent death pathways (17), e.g., heat-induced apoptosis of human fibroblasts (19) or heat-induced clonogenic cell death (67).

An intriguing question is whether chaperone function of HSP72 is necessary for protection from heat-induced killing. If HSP72 inhibits cell death by repairing labile-essential proteins, its refolding function should be necessary. On the other hand, if HSP72 acts as a suppressor of signal transduction, its refolding activity may be dispensable. Interestingly, the HSP72 mutant lacking the ATPase domain retains the ability to inhibit JNK (45, 59, 63) and protects fibroblasts from heat-induced killing (34, 54, 59). Because this mutant is unable to refold heat-damaged proteins (while being able to bind to them) (34, 54), it appears that, at least in certain cell types, the JNK-inhibiting activity of HSP72 is sufficient for protection from heat-induced cell death. In lymphoid cells, however, the similar HSP72 mutant lacking the ATPase domain fails to protect cells from heat-induced apoptosis, although it inhibits JNK (39). These data suggest that protein repair plays a more important role in protection from heat shock in lymphoid cells than in fibroblasts. Furthermore, upon JNK inhibition by the HSP72 mutant, a JNK-independent cell death pathway is triggered in lymphoid cells.

It seems that HSP72 can inhibit stress-induced JNK activation by two mechanisms. In case of protein-damaging stresses such as heat shock, ethanol, oxidative stress, or heavy metals, HSP72 acts primarily through stimulation of JNK phosphatase (36), an enzyme that inactivates JNK. With other stresses such as ultraviolet radiation, osmotic stress, or tumor necrosis factor, inhibition of JNK by HSP72 may be related to inhibition of JNK-activating kinase cascade (J. A. Yaglom et al., unpublished observations).

The suppression of JNK by HSP72 sheds new light on the phenomenon of acquired stress tolerance, i.e., that mild heat shock followed by a recovery period makes cells resistant to severe heat shock and some other stresses (see Ref. 16 for review). Mild heat shock initiates two processes: it rapidly and transiently activates JNK (and survival kinases) to a relatively low level, which is insufficient to turn on the apoptotic process, and induces slow (within several hours) accumulation of HSP72. After a recovery period, the accumulated HSP72 suppresses the activation of JNK after exposure of cells to severe stresses and these cells do not undergo apoptosis.

Beside JNK, HSP72 can suppress heat-induced activation of other MAPKs, p38 (18), and ERK (Ref. 50 and J. A. Yaglom, unpublished observations). Because p38 and ERK play protective roles (see above), HSP72 overexpression may inhibit cell survival pathways, thus potentially nullifying its inhibitory effect on the cell death pathway. However, under physiological conditions, inhibition of JNK by HSP72 appears to be more important in deciding the fate of the cell than inhibition of survival pathways.

In inhibition of ERK, HSP72 acts via binding to the protein Bag1, which normally associates with and activates an upstream component of the ERK signaling pathway (Raf1) (50). Overexpression of Bag1 cancels the ERK-inhibitory action of HSP72 and strongly activates ERK (50), leading to protection of cells from heat shock (55, 65). Interestingly, although Bag1 suppresses heat shock-induced apoptosis, it inhibits an ATPase activity of HSP70 family members, thus blocking their protein-refolding capability (43, 55). These data again reiterate that, in protection from apoptosis by HSPs, the role of HSPs in refolding of damaged proteins may not be essential, whereas the role of HSPs in the regulation of signaling pathways plays a critical role.

	OUTLOOK

TOP ABSTRACT INTRODUCTION CELL DEATH AND SURVIVAL... SIGNALING PATHWAYS REGULATE... HSPS CONTROL APOPTOTIC... OUTLOOK REFERENCES

Recent data indicate that cellular response to heat shock involves activation of various signaling pathways. The molecular mechanism of triggering of these responses is presently unclear and needs to be established. Little is known about caspase-independent apoptosis and reproductive cell death, although these processes clearly play an important role in heat-induced death in many cell types. Finally, understanding the novel function of chaperones in modulation of cell signaling, which is of fundamental importance, is just beginning to emerge, and molecular mechanisms of such regulation have yet to be studied.

	FOOTNOTES

Address for reprint requests and other correspondence: M. Y. Sherman, Dept. of Biochemistry, Boston Univ. School of Medicine, 715 Albany St., Boston, MA 02118 (E-mail: sherman{at}biochem.bumc.bu.edu).

10.1152/japplphysiol.01101.2001

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