Activation of the p38 Signaling Pathway by Heat Shock Involves the Dissociation of Glutathione S-Transferase Mu from Ask1

Despite the importance of the stress-activated protein kinase pathways in cell death and survival, it is unclear how stressful stimuli lead to their activation. In the case of heat shock, the existence of a specific mechanism of activation has been evidenced, but the molecular nature of this pathway is undefined. Here, we found that Ask1 (apoptosis signal-regulating kinase 1), an upstream activator of the stress-activated protein kinase p38 during exposure to oxidative stress and other stressful stimuli, was also activated by heat shock. Ask1 activity was required for p38 activation since overexpression of a kinase dead mutant of Ask1, Ask1(K709M), inhibited heat shock-induced p38 activation. The activation of Ask1 by oxidative stress involves the oxidation of thioredoxin, an endogenous inhibitor of Ask1. A different activation mechanism takes place during heat shock. In contrast to p38 induction by H2O2, induction by heat shock was not antagonized by pretreatment with the antioxidantN-acetyl-l-cysteine or by overexpressing thioredoxin and was not accompanied by the dissociation of thioredoxin from Ask1. Instead, heat shock caused the dissociation of glutathioneS-transferase Mu1-1 (GSTM1-1) from Ask1 and overexpression of GSTM1-1-inhibited induction of p38 by heat shock. We concluded that because of an alternative regulation by the two distinct repressors thioredoxin and GSTM1-1, Ask1 constitutes the converging point of the heat shock and oxidative stress-sensing pathways that lead to p38 activation. Despite the importance of the stress-activated protein kinase pathways in cell death and survival, it is unclear how stressful stimuli lead to their activation. In the case of heat shock, the existence of a specific mechanism of activation has been evidenced, but the molecular nature of this pathway is undefined. Here, we found that Ask1 (apoptosis signal-regulating kinase 1), an upstream activator of the stress-activated protein kinase p38 during exposure to oxidative stress and other stressful stimuli, was also activated by heat shock. Ask1 activity was required for p38 activation since overexpression of a kinase dead mutant of Ask1, Ask1(K709M), inhibited heat shock-induced p38 activation. The activation of Ask1 by oxidative stress involves the oxidation of thioredoxin, an endogenous inhibitor of Ask1. A different activation mechanism takes place during heat shock. In contrast to p38 induction by H2O2, induction by heat shock was not antagonized by pretreatment with the antioxidantN-acetyl-l-cysteine or by overexpressing thioredoxin and was not accompanied by the dissociation of thioredoxin from Ask1. Instead, heat shock caused the dissociation of glutathioneS-transferase Mu1-1 (GSTM1-1) from Ask1 and overexpression of GSTM1-1-inhibited induction of p38 by heat shock. We concluded that because of an alternative regulation by the two distinct repressors thioredoxin and GSTM1-1, Ask1 constitutes the converging point of the heat shock and oxidative stress-sensing pathways that lead to p38 activation. Jun N-terminal kinase apoptosis signal-regulating kinase 1 glutathione S-transferase GST Mu1-1 myelin basic protein N-acetyl-l-cysteine tumor necrosis factor TNF receptor-associated factor 2 thioredoxin hemagglutinin mitogen-activated protein Heat shock affects all proteins and structures but nevertheless produces a highly specific stress response aimed at protecting the cells and re-establishing homeostasis. In addition to the well characterized transcriptional activation of the genes coding for heat shock proteins (1Morimoto R.I. Jurivich D.A. Kroeger P.E. Mathur S.K. Murphy S.P. Nakai A. Sarge K. Abravaya K. Sistonen L.T. Morimoto R. Tissières A. Georgopoulos C. The Biology of Heat Shock Proteins and Molecular Chaperones. 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EMBO J. 1997; 16: 659-671Crossref PubMed Scopus (659) Google Scholar) or as an inhibitor of apoptotic processes (12Bruey J.M. Ducasse C. Bonniaud P. Ravagnan L. Susin S.A. Diaz-Latoud C. Gurbuxani S. Arrigo A.P. Kroemer G. Solary E. Garrido C. Nat. Cell Biol. 2000; 2: 645-652Crossref PubMed Scopus (852) Google Scholar, 13Garrido C. Bruey J.M. Fromentin A. Hammann A. Arrigo A.P. Solary E. FASEB J. 1999; 13: 2061-2070Crossref PubMed Scopus (451) Google Scholar, 14Pandey P. Saleh A. Nakazawa A. Kumar S. Srinivasula S.M. Kumar V. Weichselbaum R. Nalin C. Alnemri E.S. Kufe D. Kharbanda S. EMBO J. 2000; 19: 4310-4322Crossref PubMed Scopus (492) Google Scholar). Activation of the p38 pathway and phosphorylation of HSP27 occurs within minutes at elevated temperature and constitutes a very tightly regulated response (15Dorion S. Berube J. Huot J. Landry J. J. Biol. Chem. 1999; 274: 37591-37597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). After a mild heat shock, cells becomes refractory to reinduction of p38 activity by a second heat shock but remained fully responsive to reinduction by other stresses, cytokines, or growth factors (15Dorion S. Berube J. Huot J. Landry J. J. Biol. Chem. 1999; 274: 37591-37597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). The specificity of this desensitization reinforces the existence of a highly specific heat shock-sensing pathway upstream of p38. Despite its importance for cell survival, the signaling components and the molecular mechanism leading to heat shock-induced p38 activation are unknown. Little is known about the mechanisms of activation of the stress-sensitive pathways. In the case of UV light and hyperosmotic shock, activation of the stress-activated protein kinase JNK1 is triggered by an activation of the receptors for epidermal growth factor, tumor necrosis factor (TNF) α, and interleukin-1 (16Rosette C. Karin M. Science. 1996; 274: 1194-1197Crossref PubMed Scopus (947) Google Scholar). Alterations of receptor conformation by energy absorption or physical perturbation of the cell surface are thought to be the initial triggering events causing the clustering and internalization of these receptors and the subsequent subversion of signaling pathways normally used by growth factors or cytokines (16Rosette C. Karin M. Science. 1996; 274: 1194-1197Crossref PubMed Scopus (947) Google Scholar). In the case of oxidative stress, the sensing mechanism seems to act at the level of Ask1 (apoptosis signal-regulating kinase-1). Ask1 is a MAP kinase kinase kinase that can activate the MAP kinase kinases 3 and 6 leading to the activation of p38, or the MAP kinase kinases 4 and 7 leading to the activation of JNK (17Ichijo H. Nishida E. Irie K. ten Dijke P. Saitoh M. Moriguchi T. Takagi M. Matsumoto K. Miyazono K. Gotoh Y. Science. 1997; 275: 90-94Crossref PubMed Scopus (2059) Google Scholar). The redox regulatory protein thioredoxin (Trx) acts as the oxidative stress sensor for this cascade (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar). Under normal conditions, Trx in the reduced state binds to and inhibits Ask1. Upon oxidative stress, oxidation of Trx triggers its dissociation from Ask1, allowing the activation of Ask1 and the subsequent activation of downstream kinases. Here we show that Ask1 is also activated during heat shock and that this activation is responsible for p38 activation. However, heat shock activation of Ask1 does not proceed by a redox-dependent mechanism as shown for oxidative stress. Instead, a new mechanism of Ask1 activation is described involving the heat shock-induced dissociation from Ask1 of a recently identified inhibitor of Ask1, glutathione S-transferase Mu1-1 (GSTM1-1) (19Cho S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is concluded that the alternative regulation of Ask1 by the Trx or the the converging point of the heat shock and oxidative stress-sensing pathway leading to p38 activation. was from H2O2, N-acetyl-l-cysteine and myelin basic protein from was from for from and is a the from hemagglutinin protein is a the from the was from cells thioredoxin was from other used are in the of p38 J. Lambert H. Gingras-Breton G. Lavoie J.N. Huot J. Landry J. J. Cell Sci. 1997; 110: 357-368Crossref PubMed Google Scholar). p38 was from New is a for this was in the of Ask1 protein as described for J. Lambert H. Gingras-Breton G. Lavoie J.N. Huot J. Landry J. J. Cell Sci. 1997; 110: 357-368Crossref PubMed Google Scholar). is an PubMed Scopus Google Scholar). and cells in and and with or at in a cells cells the the used for all heat shock the with and a at for the of other used and the cells at for the of was used the to with The and used for of glutathione S-transferase p38, thioredoxin, a of GSTM1-1, a Ask1, and a Ask1 (17Ichijo H. Nishida E. Irie K. ten Dijke P. Saitoh M. Moriguchi T. Takagi M. Matsumoto K. Miyazono K. Gotoh Y. Science. 1997; 275: 90-94Crossref PubMed Scopus (2059) Google Scholar, S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Nishitoh H. Ichijo H. J.M. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, E. J. S. M. K. M. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). cells at a of 1 by was as described of J. P. Lambert H. Hickey E. Weber L.A. J. Cell Biol. PubMed Scopus Google Scholar). The cells and used After cells and in 1 3 and 1 The and at at 4 The and at The at 4 Ask1 an of Ask1 cell for Ask1 protein was with of for 1 and with of protein in After the for and with of 2 and 1 was by two with 2 and 1 was used for the kinase The was in of kinase 3 of and of Ask1 activity was for at and was by the addition of of activity was by of the by and a endogenous or p38 cells in Proteins by Under these conditions, the protein is from the endogenous protein to its Proteins as described (6Lavoie J.N. Lambert H. Hickey E. Weber L.A. Landry J. Mol. Cell. Biol. 1995; 15: 505-516Crossref PubMed Scopus (572) Google Scholar). After the with proteins an of the kinase different was by with After cells and in 1 and 1 The and at for at 4 The with or for 1 and the with of protein in After for and at with of Proteins and with the Heat shock activates the stress-activated protein kinase p38, but the upstream signaling pathway leading to this activation is not The MAP kinase kinase kinase Ask1 has been shown to be an upstream activator of p38 during exposure to stressful stimuli (17Ichijo H. Nishida E. Irie K. ten Dijke P. Saitoh M. Moriguchi T. Takagi M. Matsumoto K. Miyazono K. Gotoh Y. Science. 1997; 275: 90-94Crossref PubMed Scopus (2059) Google Scholar, S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. D. H. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Nishitoh H. Ichijo H. D. Science. 1998; PubMed Scopus Google Scholar, Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, H. M. T. A. S. M. Ichijo H. Miyazono K. T. 1999; PubMed Scopus Google Scholar). We heat shock also activate Ask1. Ask1 was from cells at the temperature to Ask1 activity was as Ask1 activity in a Ask1 was an of the heat shock-induced p38 activation we the of overexpressing Ask1(K709M), a mutant of Ask1, p38 activation. with and p38 and to heat shock or other known of p38. p38 activity was in cells a p38 of of p38 and of of and of inhibited heat shock-induced p38 activation in a The was In with (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar, H. Nishitoh H. Ichijo H. J.M. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar), the activation by it the activation of p38 by hyperosmotic shock or that Ask1 is an upstream activator of p38 in response to heat shock. The specificity of the that Ask1 a of the stimuli that activates p38. We that a heat shock cells to p38 activation by heat shock but fully responsive to p38 activation by cytokines, growth and (15Dorion S. Berube J. Huot J. Landry J. J. Biol. Chem. 1999; 274: 37591-37597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). the existence of a specific mechanism for p38 activation by heat shock. We this heat desensitization also Ask1 to a heat shock at and 7 to a second heat shock or to a for p38 (15Dorion S. Berube J. Huot J. Landry J. J. Biol. Chem. 1999; 274: 37591-37597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar) and a heat shock pretreatment cells for the activation of Ask1 by a second heat shock but Ask1 activation that heat shock activate Ask1 by a mechanism different from that used by Ask1 is known to be responsive to the redox We a perturbation in the redox state was a for heat shock activation of the p38 for with of the to exposure to heat shock or with at inhibited activation of p38 but the by heat shock of is an upstream of p38 activation in response to H2O2, oxidative stress is not a triggering for the induction of p38 in response to heat shock. We an endogenous inhibitor of Ask1, p38 activation by heat shock. cells with p38 and Trx and to heat shock or p38 activity was a p38 of of p38 and of of Trx by and of Trx inhibited activation of p38 in a but heat shock activation of p38. We the of heat shock the in Ask1 and cells with an or with an and to heat shock or Trx was with Trx and the by with of of and endogenous Trx and Trx and Ask1 be but not heat shock, caused a dissociation of Trx from Ask1. was recently identified as endogenous inhibitor of Ask1 activity (19Cho S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We p38 activation by heat shock. cells with p38 and and to heat shock, H2O2, or p38 phosphorylation was a p38 of of p38 and of of by and of inhibited in a heat shock-induced activation to a activation of p38. activation of p38. result was with the that is an inhibitor of Ask1 and that Ask1 was not in the activation of p38 by We the of heat shock the of Ask1 with in with and to heat shock or was with and the by of of and endogenous and The an and Ask1 Heat shock but not this The stress-activated protein kinase p38 is activated by a of different stimuli growth factors and cytokines, but also by different or as to physical or or hyperosmotic shock, stress, oxidative stress, and heat shock J. Lambert H. Gingras-Breton G. Lavoie J.N. Huot J. Landry J. J. Cell Sci. 1997; 110: 357-368Crossref PubMed Google Scholar, S. Berube J. Huot J. Landry J. J. Biol. Chem. 1999; 274: 37591-37597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, J. Houle F. S. Landry J. J. 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Here we that a heat shock also inhibits the activation of Ask1 by a subsequent heat shock, but does not activation of Ask1 by result that a activation mechanism at the level or upstream of Ask1 that is distinct from that used by distinct mechanisms of Ask1 activation are in activates the by the oxidation of the protein Trx (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar). In cells Trx binds to Ask1, an that Ask1 in an is the redox of of Trx the allowing the activation of Ask1 by and Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). also the of an kinase in this K. Saitoh M. Ichijo H. J. Cell. PubMed Scopus Google Scholar). A mechanism is in activation of Ask1 H. Saitoh M. Y. Takeda K. H. M. Miyazono K. Ichijo H. Mol. Cell. 1998; 2: Full Text Full Text PDF PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). in response to TNF the dissociation of Trx from Ask1, the of TNF receptor-associated factor 2 to Ask1 and its activation Activation of Ask1 be in with the overexpression of Trx H. Saitoh M. Y. Takeda K. H. M. Miyazono K. Ichijo H. Mol. Cell. 1998; 2: Full Text Full Text PDF PubMed Scopus Google 1999; PubMed Scopus Google Scholar). In contrast to activation of p38 by heat shock was not antagonized by pretreatment with the or by overexpression of Trx A and in contrast to H2O2, heat shock not a dissociation of Trx from Ask1 Instead, we found that heat shock-induced activation of Ask1 involves the of GSTM1-1, a endogenous inhibitor of Ask1 activity (19Cho S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was that Ask1 activity by to the kinase and its The of Ask1 activity by was to be the of in the level of of In it was that induction of stress in a mechanism to Ask1 protecting the cells from apoptosis (19Cho S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a regulation of activity by heat shock. We that heat shock the of from Ask1 The dissociation of from Ask1 is not by that the dissociation is not a of Ask1 activation. Instead, the dissociation of triggers Ask1 activation since overexpression of inhibited p38 activation by heat shock in a heat shock-induced dissociation of from Ask1 is of and dissociation of Trx from Ask1 (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar, H. Nishitoh H. Ichijo H. J.M. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). A mechanism of activation has also been described for and JNK is by oxidative stress caused by the of and and the dissociation to activity V. M. L. M. EMBO J. 1999; PubMed Scopus Google Scholar). is to that to which acts as a of Ask1, acts as a of Ask1, and its dissociation heat shock to Ask1 activation. The mechanisms that lead to the dissociation of from Ask1 and it can also be by other heat shock to be The of from Ask1 as well as of its activity a mutant with glutathione S-transferase activity (19Cho S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), that this activity was not in the regulation of Ask1. GST activity in the of glutathione to In addition to their activity GST proteins an as of a of as and their G. PubMed Scopus Google Scholar, Biochem. Mol. Biol. 1995; PubMed Scopus Google Scholar). is that during heat shock are or in a that with Ask1 for to the of Trx from Ask1 in the case of H2O2, the of during heat shock may subsequent Ask1 activation by However, the of this inhibitor may not be for activation of Ask1. In the case of TNF the of the activator is required for Ask1 activation H. Saitoh M. Y. Takeda K. H. M. Miyazono K. Ichijo H. Mol. Cell. 1998; 2: Full Text Full Text PDF PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). Ask1 activation by heat shock may the of a activator in addition to its dissociation from a result of this alternative regulation by Trx and GSTM1-1, Ask1 can the converging point of the heat shock and oxidative stress-sensing pathways leading to p38 activation. The nature of this regulation to be heat shock and the of of the it be that Trx can by Ask1 and that the of is for activation. A is that Trx and are by fully as but that in the cells different of Ask1 at to Trx and responsive to oxidative stress and to and responsive to heat shock is because to the N-terminal of Ask1 (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar, S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and may for the the of regulatory known to Ask1 (18Saitoh M. Nishitoh H. Fujii M. Takeda K. Tobiume K. Sawada Y. Kawabata M. Miyazono K. Ichijo H. EMBO J. 1998; 17: 2596-2606Crossref PubMed Scopus (2112) Google Scholar, S.G. K. J. S.J. Kim J. Kim Y. Kim S.G. Ichijo H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Nishitoh H. Ichijo H. D. Science. 1998; PubMed Scopus Google Scholar, H. Saitoh M. Y. Takeda K. H. M. Miyazono K. Ichijo H. Mol. 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The of Ask1 at the converging point of sensing pathways be in cell in the light of the recently of Ask1 in cell and apoptosis A. Ichijo H. J. Biochem. PubMed Scopus Google Scholar). We H. Ichijo for the Ask1 and M. for the

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