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• W2149721868 abstract "Accumulation of misfolded proteins and alterations in Ca2+ homeostasis in the endoplasmic reticulum (ER) causes ER stress and leads to cell death. However, the signal-transducing events that connect ER stress to cell death pathways are incompletely understood. To discern the pathway by which ER stress-induced cell death proceeds, we performed studies on Apaf-1−/− (null) fibroblasts that are known to be relatively resistant to apoptotic insults that induce the intrinsic apoptotic pathway. While these cells were resistant to cell death initiated by proapoptotic stimuli such as tamoxifen, they were susceptible to apoptosis induced by thapsigargin and brefeldin-A, both of which induce ER stress. This pathway was inhibited by catalytic mutants of caspase-12 and caspase-9 and by a peptide inhibitor of caspase-9 but not by caspase-8 inhibitors. Cleavage of caspases and poly(ADP-ribose) polymerase was observed in cell-free extracts lacking cytochrome c that were isolated from thapsigargin or brefeldin-treated cells. To define the molecular requirements for this Apaf-1 and cytochrome c-independent apoptosis pathway further, we developed a cell-free system of ER stress-induced apoptosis; the addition of microsomes prepared from ER stress-induced cells to a normal cell extract lacking mitochondria or cytochromec resulted in processing of caspases. Immunodepletion experiments suggested that caspase-12 was one of the microsomal components required to activate downstream caspases. Thus, ER stress-induced programmed cell death defines a novel, mitochondrial and Apaf-1-independent, intrinsic apoptotic pathway. Accumulation of misfolded proteins and alterations in Ca2+ homeostasis in the endoplasmic reticulum (ER) causes ER stress and leads to cell death. However, the signal-transducing events that connect ER stress to cell death pathways are incompletely understood. To discern the pathway by which ER stress-induced cell death proceeds, we performed studies on Apaf-1−/− (null) fibroblasts that are known to be relatively resistant to apoptotic insults that induce the intrinsic apoptotic pathway. While these cells were resistant to cell death initiated by proapoptotic stimuli such as tamoxifen, they were susceptible to apoptosis induced by thapsigargin and brefeldin-A, both of which induce ER stress. This pathway was inhibited by catalytic mutants of caspase-12 and caspase-9 and by a peptide inhibitor of caspase-9 but not by caspase-8 inhibitors. Cleavage of caspases and poly(ADP-ribose) polymerase was observed in cell-free extracts lacking cytochrome c that were isolated from thapsigargin or brefeldin-treated cells. To define the molecular requirements for this Apaf-1 and cytochrome c-independent apoptosis pathway further, we developed a cell-free system of ER stress-induced apoptosis; the addition of microsomes prepared from ER stress-induced cells to a normal cell extract lacking mitochondria or cytochromec resulted in processing of caspases. Immunodepletion experiments suggested that caspase-12 was one of the microsomal components required to activate downstream caspases. Thus, ER stress-induced programmed cell death defines a novel, mitochondrial and Apaf-1-independent, intrinsic apoptotic pathway. endoplasmic reticulum benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone benzyloxycarbonyl-Leu-Glu(OMe)-His-Asp(OMe)-fluoromethyl ketone glucose-regulated protein poly(ADP-ribose) polymerase human embryonic kidney cells immortalized with Simian virus 40 large tumor antigen Apaf-1−/−immortalized mouse embryonic fibroblasts mouse embryonic fibroblast cell line NIH3T3 The endoplasmic reticulum (ER)1 is a principal site for protein synthesis and folding and also serves as a cellular storage site for calcium (1Paschen W. Cell Calcium. 2001; 29: 1-11Crossref PubMed Scopus (140) Google Scholar). Perturbation of Ca2+ homeostasis, increased production of free radicals, inhibition of protein glycosylation, and accumulation of misfolded proteins in the ER can all elicit cellular stress responses, particularly ER stress signals, to protect cells against changes in Ca2+ levels and toxic buildup of misfolded proteins (1Paschen W. Cell Calcium. 2001; 29: 1-11Crossref PubMed Scopus (140) Google Scholar, 2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1919) Google Scholar, 3Mattson M.P. LaFerla F.M. Chan S.L. Leissring M.A. Shepel P.N. Geiger J.D. Trends Neurosci. 2000; 23: 222-229Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). Prolonged ER stress leads to cell death and is linked to the pathogenesis of some neurodegenerative disorders that feature misfolded proteins, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (3Mattson M.P. LaFerla F.M. Chan S.L. Leissring M.A. Shepel P.N. Geiger J.D. Trends Neurosci. 2000; 23: 222-229Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar, 4Sherman M.Y. Goldberg A.L. Neuron. 2001; 29: 15-32Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar). Activation of caspases, a family of cysteine proteases with aspartate P1 specificity, is a central mechanism in the apoptotic cell death process (5Alnemri E.S. Livingston D.J. Nicholson D.W. Salvesen G. Thornberry N.A. Wong W.W. Yuan J. Cell. 1996; 87: 171Abstract Full Text Full Text PDF PubMed Scopus (2129) Google Scholar). The extrinsic pathway of caspase activation involves signal transduction through cellular death receptors such as Fas, resulting in caspase-8 activation, which in turn activates downstream effector caspases such as caspase-3 and caspase-7 (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar). The intrinsic pathway involves release of the mitochondrial protein cytochrome c, which forms an oligomeric complex with dATP and Apaf-1 (7Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6182) Google Scholar, 8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar). It is this oligomeric complex that recruits procaspase-9 directly, activates it, and then releases active caspase-9 from the complex to set in motion the caspase-9-dependent activation of effector caspases such as caspase-3, -6, and -7 (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar, 8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar, 9Saleh A. Srinivasula S.M. Acharya S. Fishel R. Alnemri E.S. J. Biol. Chem. 1999; 274: 17941-17945Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Once active, the effector caspases cleave various cellular targets, including poly(ADP-ribose) polymerase (10Lazebnik Y.A. Kaufmann S.H. Desnoyers S. Poirier G.G. Earnshaw W.C. Nature. 1994; 371: 346-347Crossref PubMed Scopus (2339) Google Scholar) and other substrates (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar), ultimately leading to cell death. Earlier studies have demonstrated a molecular link between ER stress and caspase-12 activation, resulting in increased cell death (11Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1032) Google Scholar, 12Nakagawa T. Zhu H. Morishima N., Li, E., Xu, J. Yankner B.A. Yuan J. Nature. 2000; 403: 98-103Crossref PubMed Scopus (2926) Google Scholar, 13Yoneda T. Imaizumi K. Oono K. Yui D. Gomi F. Katayama T. Tohyama M. J. Biol. Chem. 2001; 276: 13935-13940Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar, 14Rao R.V. Hermel E. Castro-Obregon S. del Rio G. Ellerby L.M. Ellerby H.M. Bredesen D.E. J. Biol. Chem. 2001; 276: 33869-33874Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 15Rao R. Peel A. Logvinova A. del Rio Guerra G. Hermel E. Yokota T. Goldsmith P. Ellerby L. Ellerby H.M. Bredesen D. FEBS Lett. 2002; 514: 122-128Crossref PubMed Scopus (499) Google Scholar). However, the downstream targets of caspase-12 yet remain to be identified. Therefore, the question arose as to whether activation of downstream caspases and cell death following ER stress involves the previously described extrinsic pathway, the mitochondria-dependent intrinsic apoptotic pathway, or an alternate pathway (16Sperandio S. de Belle I. Bredesen D.E. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 14376-14381Crossref PubMed Scopus (777) Google Scholar, 17Leist M. Jaattela M. Nat. Rev. Mol. Cell. Biol. 2001; 2: 589-598Crossref PubMed Scopus (1376) Google Scholar).In the present study, we investigated the mechanism of ER stress-induced activation of caspases and cell death in Sak2 cells, which are Apaf-1 null cells (18Yoshida H. Kong Y.Y. Yoshida R. Elia A.J. Hakem A. Hakem R. Penninger J.M. Mak T.W. Cell. 1998; 94: 739-750Abstract Full Text Full Text PDF PubMed Scopus (993) Google Scholar, 19Cecconi F. Alvarez-Bolado G. Meyer B.I. Roth K.A. Gruss P. Cell. 1998; 94: 727-737Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar). Sak2 cells are generally more resistant to cell death initiated by various apoptotic agents, including those that utilize Fas or ceramide-mediated pathways (18Yoshida H. Kong Y.Y. Yoshida R. Elia A.J. Hakem A. Hakem R. Penninger J.M. Mak T.W. Cell. 1998; 94: 739-750Abstract Full Text Full Text PDF PubMed Scopus (993) Google Scholar,19Cecconi F. Alvarez-Bolado G. Meyer B.I. Roth K.A. Gruss P. Cell. 1998; 94: 727-737Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar). We demonstrate that treatment of Sak2 cells with thapsigargin or brefeldin-A induces ER stress, activation of caspase-12, and cell death. ER stress-induced caspase-12-mediated cell death proceeds in a caspase-9-dependent pathway yet by a mechanism that is independent of the previously described intrinsic (mitochondria-dependent) apoptotic pathway (7Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6182) Google Scholar, 8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar). ER stress-induced cell death was inhibited by catalytic mutants of caspase-12 and caspase-9 and by the peptide inhibitor of caspase-9 but not by inhibition of caspase-8. We also developed a cell-free model of ER stress-induced cell death that involves the addition of microsomes to a 300,000 × g cell-free extract that not only lacks Apaf-1 but also cytochrome c, both of which are required for activating caspase-9 and other downstream caspases through the previously described intrinsic apoptotic pathway. This system was capable of reproducing a key element of apoptosis, namely caspase processing and activation. Caspase-12 was identified as one of the microsomal components required for downstream caspase processing. Thus, ER stress-induced caspase-12 activation defines a novel, ER-based intrinsic pathway for apoptosome-independent effector caspase activation and cell death.DISCUSSIONApoptosis typically proceeds through one of two general signaling pathways, namely the extrinsic apoptotic pathway or the intrinsic apoptotic pathway. In the former case, binding of specific death ligands to their receptors causes oligomerization of death receptors, resulting in recruitment of adaptor molecules involved in activation of caspase-8. In the latter case, when the mitochondrion receives appropriate apoptotic signals, cytochrome c is released into the cytosol (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar, 32Budihardjo I. Oliver H. Lutter M. Luo X. Wang X. Annu. Rev. Cell Dev. Biol. 1999; 15: 269-290Crossref PubMed Scopus (2249) Google Scholar). Earlier studies have shown that together with dATP and cytochrome c, Apaf-1 forms a multimeric complex that activates procaspase-9 (8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar, 9Saleh A. Srinivasula S.M. Acharya S. Fishel R. Alnemri E.S. J. Biol. Chem. 1999; 274: 17941-17945Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). The formation of this complex occurs through a multistep process and serves as a key commitment step for activation of caspase-9 and downstream caspases. Caspase-9 activation and its release from the multimeric complex requires a fully functional Apaf-1 protein (8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar, 9Saleh A. Srinivasula S.M. Acharya S. Fishel R. Alnemri E.S. J. Biol. Chem. 1999; 274: 17941-17945Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Activated caspase-8 and caspase-9 in turn activate executioner caspases, including caspase-3. Cell death is thought to result from the proteolysis of cellular substrates by active caspase-3 and -7 (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar, 33Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5112) Google Scholar, 34Song Z. Steller H. Trends Cell Biol. 1999; 9: M49-M52Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). There has been some controversy over the role of mitochondria in apoptosis; it is believed by some that the primary apoptotic signals communicate directly with the cytosolic caspases, with the mitochondria contributing only a secondary role in the apoptotic process (35Finkel E. Science. 2001; 292: 624-626Crossref PubMed Scopus (170) Google Scholar). Therefore, in addition to Apaf-1 and cytochrome c, alternate mechanisms may be involved in the activation of procaspase-9.Like the mitochondria, the endoplasmic reticulum is a repository for both proapoptotic and antiapoptotic molecules. The known proapoptotic molecules include caspase-12 (11Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1032) Google Scholar, 12Nakagawa T. Zhu H. Morishima N., Li, E., Xu, J. Yankner B.A. Yuan J. Nature. 2000; 403: 98-103Crossref PubMed Scopus (2926) Google Scholar, 14Rao R.V. Hermel E. Castro-Obregon S. del Rio G. Ellerby L.M. Ellerby H.M. Bredesen D.E. J. Biol. Chem. 2001; 276: 33869-33874Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar), p28Bap31 (36Ng F.W. Nguyen M. Kwan T. Branton P.E. Nicholson D.W. Cromlish J.A. Shore G.C. J. Cell Biol. 1997; 139: 327-338Crossref PubMed Scopus (287) Google Scholar), and GADD153 (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1919) Google Scholar), whereas the antiapoptotic molecules identified to date include the ER chaperone proteins GRP78 (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1919) Google Scholar), calreticulin (37Ozawa K. Kuwabara K. Tamatani M. Takatsuji K. Tsukamoto Y. Kaneda S. Yanagi H. Stern D.M. Eguchi Y. Tsujimoto Y. Ogawa S. Tohyama M. J. Biol. Chem. 1999; 274: 6397-6404Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), protein-disulfide isomerase, and ORP-150 (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1919) Google Scholar, 25Liu H. Bowes 3rd, R.C. van de Water B. Sillence C. Nagelkerke J.F. Stevens J.L. J. Biol. Chem. 1997; 272: 21751-21759Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 38Tanaka S. Uehara T. Nomura Y. J. Biol. Chem. 2000; 275: 10388-10393Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar) as well as DAD1 (39Brewster J.L. Martin S.L. Toms J. Goss D. Wang K. Zachrone K. Davis A. Carlson G. Hood L. Coffin J.D. Genesis. 2000; 26: 271-278Crossref PubMed Scopus (37) Google Scholar, 40Hong N.A. Flannery M. Hsieh S.N. Cado D. Pedersen R. Winoto A. Dev. Biol. 2000; 220: 76-84Crossref PubMed Scopus (61) Google Scholar). Despite the identification of these apoptotic regulators, the pathways that connect ER stress to apoptotic cell death remain unclear. Earlier reports indicated that ER stress induces the formation of a GRP78·procaspase-12·procaspase-7 complex (15Rao R. Peel A. Logvinova A. del Rio Guerra G. Hermel E. Yokota T. Goldsmith P. Ellerby L. Ellerby H.M. Bredesen D. FEBS Lett. 2002; 514: 122-128Crossref PubMed Scopus (499) Google Scholar). Prolonged stress can result in the disruption of this multimeric complex and the release of active caspase-12 that may activate caspase-9 and lead to apoptosis (14Rao R.V. Hermel E. Castro-Obregon S. del Rio G. Ellerby L.M. Ellerby H.M. Bredesen D.E. J. Biol. Chem. 2001; 276: 33869-33874Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 15Rao R. Peel A. Logvinova A. del Rio Guerra G. Hermel E. Yokota T. Goldsmith P. Ellerby L. Ellerby H.M. Bredesen D. FEBS Lett. 2002; 514: 122-128Crossref PubMed Scopus (499) Google Scholar). Other activators of caspase-12 include the IRE1-TRAF2 complex (13Yoneda T. Imaizumi K. Oono K. Yui D. Gomi F. Katayama T. Tohyama M. J. Biol. Chem. 2001; 276: 13935-13940Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar) and calpain (11Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1032) Google Scholar), both in response to ER stress. However, earlier studies have also suggested that calpains act as negative regulators of caspase processing by inactivating caspase-9 and -3 (41Chua B.T. Guo K. Li P. J. Biol. Chem. 2000; 275: 5131-5135Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 42Lankiewicz S. Marc Luetjens C. Truc Bui N. Krohn A.J. Poppe M. Cole G.M. Saido T.C. Prehn J.H. J. Biol. Chem. 2000; 275: 17064-17071Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Thus, while calpains may be required for caspase-12 activation, they may not have a role in the caspase cascade leading to cell death. Activation of caspase-12, by any of the above mechanisms, may therefore initiate downstream caspase processing, activation, and cell death. It is thus important to understand how the caspase-7/caspase-12 pathway differs from the calpain/caspase-12 pathway as well as the relevance of each of these pathways in ER stress-induced cell death. Studies employing calpain and caspase site-specific antibodies to caspase-12 may prove useful to elucidate these specific pathways.The present study was undertaken to characterize the biochemical pathway by which ER stress leads to apoptosis. The studies were carried out in Apaf-1−/− cells that are known to be relatively resistant to apoptotic insults that induce the intrinsic pathway. The cell-free extracts from these cells lacked mitochondria and cytochromec and thus provided a system to assess whether ER stress-mediated apoptosis is triggered by the activation of caspases without the involvement of the apoptosome. Our studies indicate that Apaf-1−/− cells are sensitive to ER stress inducers, undergo classical apoptosis, and possess features typical of caspase activation. Studies on whole cells, cell-free cytosolic extracts, and cell-free extracts containing primed microsomes suggest a role for caspase-12 in caspase-9 activation that is independent of Apaf-1 and mitochondria. Studies are in progress to identify other microsomal components that act in concert with caspase-12 to mediate ER stress-induced cell death.Whereas our studies rule out a requirement for cytochromec in the activation of caspases by ER stress, it is possible that prolonged ER stress may involve the concerted action of mitochondria and cytochrome c in caspase activation and cell death. In this context, several reports have demonstrated that thapsigargin induces cytochrome c release from mitochondria in murine and human cells (43Koya R.C. Fujita H. Shimizu S. Ohtsu M. Takimoto M. Tsujimoto Y. Kuzumaki N. J. Biol. Chem. 2000; 275: 15343-15349Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 44Nakamura K. Bossy-Wetzel E. Burns K. Fadel M.P. Lozyk M. Goping I.S. Opas M. Bleackley R.C. Green D.R. Michalak M. J. Cell Biol. 2000; 150: 731-740Crossref PubMed Scopus (245) Google Scholar, 45Wei M.C. Zong W.X. Cheng E.H. Lindsten T. Panoutsakopoulou V. Ross A.J. Roth K.A. MacGregor G.R. Thompson C.B. Korsmeyer S.J. Science. 2001; 292: 727-730Crossref PubMed Scopus (3316) Google Scholar). However, in these studies, the activation of downstream caspases proceeded with the active involvement of cytochrome c and Apaf-1 (apoptosome). In the absence of Apaf-1, other modes of caspase activation may exist. The current studies involving caspase-12 highlight one such mechanism. In addition to our present work, other studies have also demonstrated alternative mechanisms for caspase activation in the absence of Apaf-1 and cytochrome c (16Sperandio S. de Belle I. Bredesen D.E. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 14376-14381Crossref PubMed Scopus (777) Google Scholar, 46Burgess D.H. Svensson M. Dandrea T. Gronlund K. Hammarquist F. Orrenius S. Cotgreave I.A. Cell Death Differ. 1999; 6: 256-261Crossref PubMed Scopus (57) Google Scholar, 47Chauhan D. Hideshima T. Rosen S. Reed J.C. Kharbanda S. Anderson K.C. J. Biol. Chem. 2001; 276: 24453-24456Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 48Forcet C., Ye, X. Granger L. Corset V. Shin H. Bredesen D.E. Mehlen P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3416-3421Crossref PubMed Scopus (174) Google Scholar). These studies demonstrated activation of caspase-9 by a mitochondrial component (47Chauhan D. Hideshima T. Rosen S. Reed J.C. Kharbanda S. Anderson K.C. J. Biol. Chem. 2001; 276: 24453-24456Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar) or by a proapoptotic receptor complex (16Sperandio S. de Belle I. Bredesen D.E. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 14376-14381Crossref PubMed Scopus (777) Google Scholar, 48Forcet C., Ye, X. Granger L. Corset V. Shin H. Bredesen D.E. Mehlen P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3416-3421Crossref PubMed Scopus (174) Google Scholar).Whereas the mechanism of ER stress-mediated activation of caspase-12 and other downstream caspases may be relevant in understanding neurodegenerative disorders that feature misfolded proteins, any potential advances in understanding these phenomena may seem irrelevant given the fact that to date there has been no report describing the sequence of human caspase-12. However, earlier observations in HeLa cells (12Nakagawa T. Zhu H. Morishima N., Li, E., Xu, J. Yankner B.A. Yuan J. Nature. 2000; 403: 98-103Crossref PubMed Scopus (2926) Google Scholar), A549 human lung carcinoma cells (49Bitko V. Barik S. J. Cell. Biochem. 2001; 80: 441-454Crossref PubMed Scopus (133) Google Scholar), and 293T cells (14Rao R.V. Hermel E. Castro-Obregon S. del Rio G. Ellerby L.M. Ellerby H.M. Bredesen D.E. J. Biol. Chem. 2001; 276: 33869-33874Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar) and studies in progress indicate that there exists a “human caspase-12-like protein” that is recognized by mouse caspase-12 antibodies. The human caspase-12 like protein has a similar molecular mass as the mouse caspase-12 and exists as a phosphorylated protein. 2R. V. Rao, S. Castro-Obregons, H. Frankowski, M. Schuler, V. Stoka, G. del Rio, D. E. Bredesen, and H. M. Ellerby, unpublished data. Studies are in progress to further characterize and identify this protein, which may have a key role in ER stress and neurodegeneration. The endoplasmic reticulum (ER)1 is a principal site for protein synthesis and folding and also serves as a cellular storage site for calcium (1Paschen W. Cell Calcium. 2001; 29: 1-11Crossref PubMed Scopus (140) Google Scholar). Perturbation of Ca2+ homeostasis, increased production of free radicals, inhibition of protein glycosylation, and accumulation of misfolded proteins in the ER can all elicit cellular stress responses, particularly ER stress signals, to protect cells against changes in Ca2+ levels and toxic buildup of misfolded proteins (1Paschen W. Cell Calcium. 2001; 29: 1-11Crossref PubMed Scopus (140) Google Scholar, 2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1919) Google Scholar, 3Mattson M.P. LaFerla F.M. Chan S.L. Leissring M.A. Shepel P.N. Geiger J.D. Trends Neurosci. 2000; 23: 222-229Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). Prolonged ER stress leads to cell death and is linked to the pathogenesis of some neurodegenerative disorders that feature misfolded proteins, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (3Mattson M.P. LaFerla F.M. Chan S.L. Leissring M.A. Shepel P.N. Geiger J.D. Trends Neurosci. 2000; 23: 222-229Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar, 4Sherman M.Y. Goldberg A.L. Neuron. 2001; 29: 15-32Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar). Activation of caspases, a family of cysteine proteases with aspartate P1 specificity, is a central mechanism in the apoptotic cell death process (5Alnemri E.S. Livingston D.J. Nicholson D.W. Salvesen G. Thornberry N.A. Wong W.W. Yuan J. Cell. 1996; 87: 171Abstract Full Text Full Text PDF PubMed Scopus (2129) Google Scholar). The extrinsic pathway of caspase activation involves signal transduction through cellular death receptors such as Fas, resulting in caspase-8 activation, which in turn activates downstream effector caspases such as caspase-3 and caspase-7 (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar). The intrinsic pathway involves release of the mitochondrial protein cytochrome c, which forms an oligomeric complex with dATP and Apaf-1 (7Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6182) Google Scholar, 8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar). It is this oligomeric complex that recruits procaspase-9 directly, activates it, and then releases active caspase-9 from the complex to set in motion the caspase-9-dependent activation of effector caspases such as caspase-3, -6, and -7 (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar, 8Zou H., Li, Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1783) Google Scholar, 9Saleh A. Srinivasula S.M. Acharya S. Fishel R. Alnemri E.S. J. Biol. Chem. 1999; 274: 17941-17945Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar). Once active, the effector caspases cleave various cellular targets, including poly(ADP-ribose) polymerase (10Lazebnik Y.A. Kaufmann S.H. Desnoyers S. Poirier G.G. Earnshaw W.C. Nature. 1994; 371: 346-347Crossref PubMed Scopus (2339) Google Scholar) and other substrates (6Earnshaw W.C. Martins L.M. Kaufmann S.H. Annu. Rev. Biochem. 1999; 68: 383-424Crossref PubMed Scopus (2428) Google Scholar), ultimately leading to cell death. Earlier studies have demonstrated a molecular link between ER stress and caspase-12 activation, resulting in increased cell death (11Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1032) Google Scholar, 12Nakagawa T. Zhu H. Morishima N., Li, E., Xu, J. Yankner B.A. Yuan J. Nature. 2000; 403: 98-103Crossref PubMed Scopus (2926) Google Scholar, 13Yoneda T. Imaizumi K. Oono K. Yui D. Gomi F. Katayama T. Tohyama M. J. 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