Ubiquitous Calpains Promote Caspase-12 and JNK Activation during Endoplasmic Reticulum Stress-induced Apoptosis

Ubiquitously expressed μ- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of μ- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation. Ubiquitously expressed μ- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of μ- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation. Calpains are a family of Ca2+-dependent intracellular cysteine proteases. By cleaving their protein substrates, ubiquitously expressed μ-calpain and m-calpain are implicated in a wide variety of biological functions including cell migration, cell cycle regulation, differentiation, and apoptosis (reviewed in Ref. 1Goll D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2305) Google Scholar). Both μ- and m-calpains are heterodimers, consisting of a distinct large 80-kDa catalytic subunit, encoded by the genes capn1 and capn2, respectively, and a common small 28-kDa regulatory subunit encoded by the capn4 gene. The small subunit is essential to calpain activities, as shown by in vitro biochemical studies where a 25-amino acid truncation at the C terminus abolished all detectable calpain activity (2Elce J.S. Davies P.L. Hegadorn C. Maurice D.H. Arthur J.S. Biochem. J. 1997; 326: 31-38Crossref PubMed Scopus (46) Google Scholar). This provided the rationale for the first reported capn4 knock-out mouse model, which interrupted the coding sequences in exon 9 (3Arthur J.S. Greer P.A. Elce J.S. Biochim. Biophys. Acta. 1998; 1388: 247-252Crossref PubMed Scopus (17) Google Scholar, 4Arthur J.S. Elce J.S. Hegadorn C. Williams K. Greer P.A. Mol. Cell. Biol. 2000; 20: 4474-4481Crossref PubMed Scopus (292) Google Scholar) and was predicted to truncate 38 C-terminal amino acids from the small subunit. The resulting hypothetical small subunit was not detectable, the steady-state levels of μ-80, m-80 catalytic subunits were reduced, and no calpain activity was observed (4Arthur J.S. Elce J.S. Hegadorn C. Williams K. Greer P.A. Mol. Cell. Biol. 2000; 20: 4474-4481Crossref PubMed Scopus (292) Google Scholar). More recently, we have developed a conditionally targeted capn4 locus by inserting loxP sites into intron 8 and the noncoding region of exon 11. 2Y. Tan, N. Dourdin, C. Wu, T. De Veyra, J. S. Elce, and P. A. Greer, submitted publication.2Y. Tan, N. Dourdin, C. Wu, T. De Veyra, J. S. Elce, and P. A. Greer, submitted publication. This allows conditional knock-out of capn4 by Cre-mediated recombination. Although a hypothetical small subunit protein with a 60-amino acid deletion at the C terminus might still be produced, no detectable small subunit was detected, probably because of destabilization of the hypothetical truncated protein. Expression of the large subunits was also greatly diminished, supporting the proposed role for the small subunit in stabilizing large subunits. As expected, mouse embryonic fibroblasts (MEFs) 3The abbreviations used are: MEF, mouse embryonic fibroblast; ER, endoplasmic reticulum; TG, thapsigargin; TN, tunicamycin; MAP kinase, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; ASK1, apoptosis signal-regulating kinase 1; E, embryonic day; CMV, cytomegalovirus; Cre, Cre recombinase; 7-AAD, 7-aminoactinomycin D; PE, phycoerythrin; AO, acridine orange; IRES, internal ribosome entry site; PARP, polyADP-ribose polymerase; PIPES, 1,4-piperazinediethanesulfonic acid; GFP, green fluorescent protein; TNF, tumor necrosis factor.3The abbreviations used are: MEF, mouse embryonic fibroblast; ER, endoplasmic reticulum; TG, thapsigargin; TN, tunicamycin; MAP kinase, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; ASK1, apoptosis signal-regulating kinase 1; E, embryonic day; CMV, cytomegalovirus; Cre, Cre recombinase; 7-AAD, 7-aminoactinomycin D; PE, phycoerythrin; AO, acridine orange; IRES, internal ribosome entry site; PARP, polyADP-ribose polymerase; PIPES, 1,4-piperazinediethanesulfonic acid; GFP, green fluorescent protein; TNF, tumor necrosis factor. from these knockouts also lacked any detectable ubiquitous calpain activity. 2Y. Tan, N. Dourdin, C. Wu, T. De Veyra, J. S. Elce, and P. A. Greer, submitted publication. Many reports on calpain function are based on using small molecule inhibitors, which lack specificity. In contrast, this genetic knock-out model is completely selective, and therefore provides a powerful tool to address the physiological functions of the ubiquitous calpains. Ubiquitous μ- and m-calpains have been suggested to participate in apoptosis by cleaving either pro-apoptotic or anti-apoptotic proteins like p53, Bcl-2, and Bax, depending on the nature of the stimuli and type of cells involved (6Benetti R. Del Sal G. Monte M. Paroni G. Brancolini C. Schneider C. EMBO J. 2001; 20: 2702-2714Crossref PubMed Scopus (100) Google Scholar, 7Chen M. He H. Zhan S. Krajewski S. Reed J.C. Gottlieb R.A. J. Biol. Chem. 2001; 276: 30724-30728Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 8Wood D.E. Thomas A. Devi L.A. Berman Y. Beavis R.C. Reed J.C. Newcomb E.W. Oncogene. 1998; 17: 1069-1078Crossref PubMed Scopus (303) Google Scholar). Among these studies, m-calpain was proposed to play a role in a distinct apoptotic pathway initiated by ER stress (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). The ER plays key roles in protein biosynthesis, modification, folding, and trafficking, and it is also the major pool for calcium storage. Perturbation of ER homeostasis abolishes protein folding, and the consequent accumulation of unfolded proteins in the ER imposes so called ER stress on the cell. The ER membrane residing proteins IRE1, Perk, and ATF6 are ER stress sensors, which are maintained in an inactive monomeric state by binding to the chaperone protein Bip. During ER stress, the release of Bip activates these sensors to convey their protective responses, known as the unfolded protein response (UPR). This includes enhancing the transcription of genes encoding ER chaperones and the attenuation of general protein synthesis (10Ma Y. Hendershot L.M. Cell. 2001; 107: 827-830Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar). Autophosphorylated IRE1 possesses an endoribonuclease activity that alternatively splices the mRNA encoding the transcription factor XBP-1, thus turning on chaperone genes (11Calfon M. Zeng H. Urano F. Till J.H. Hubbard S.R. Harding H.P. Clark S.G. Ron D. Nature. 2002; 415: 92-96Crossref PubMed Scopus (2067) Google Scholar). The activated Perk kinase phosphorylates eIF-2α and inhibits general protein synthesis (12Harding H.P. Zhang Y. Ron D. Nature. 1999; 397: 271-274Crossref PubMed Scopus (2457) Google Scholar). Also, the unfolded proteins trigger ATF6 cleavage by the Site-1 and Site-2 proteases to release its cytoplasmic domain, which the and activates Bip transcription J. R. R. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). ER stress be induced by as the calcium the the the ER to and of as M. M. Oncogene. 2003; PubMed Scopus Google Scholar). ER stress trigger apoptosis the activation of which on the of ER and is and activated ER stress T. H. N. Li J. Yuan J. Nature. 2000; PubMed Scopus Google Scholar). As an caspase-12 the activation of and in a and N. K. H. T. Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. H. M. G. D.E. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). knock-out cells are to ER stress-induced apoptosis T. H. N. Li J. Yuan J. Nature. 2000; PubMed Scopus Google Scholar). In vitro biochemical and calpain studies in cells suggested that m-calpain is for the cleavage of caspase-12 ER stress (9Nakagawa T. Yuan J. J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). in are to to type The c-Jun N-terminal kinase pathway is also activated in response to ER stress by IRE1, a kinase, which IRE1 factor which in activates the apoptosis signal-regulating kinase ASK1, which in activates the F. A. Zhang Y. P. Harding H.P. Ron D. 2000; PubMed Scopus Google Scholar, H. A. K. K. K. K. S. A. H. 2002; PubMed Scopus Google Scholar, H. M. Y. K. H. M. K. H. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Although the role of JNK in ER stress is not JNK activation pro-apoptotic functions of cell including and Y. Y. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. S. H. M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). knock-out which are not of the pathway ER stress are to apoptosis F. M. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this we the role of the ubiquitous calpains in ER from conditional capn4 knock-out were used to a role for calpain in key ER stress apoptosis that were to and apoptosis. This resistance correlated with a in the activation of the and the cascade. compelling genetic and biochemical evidence for a role for calpain in the of from the ER to the caspase-12 apoptotic pathway and JNK activation. and acridine were from was from and was from Bcl-2, Bax, and were from both the large and small subunits of m-calpain was (4Arthur J.S. Elce J.S. Hegadorn C. Williams K. Greer P.A. Mol. Cell. Biol. 2000; 20: 4474-4481Crossref PubMed Scopus (292) Google Scholar). The was De T. A. P. Elce J.S. PubMed Scopus Google Scholar). of a targeted capn4 is calpain small subunit coding sequences in and were by loxP internal ribosome entry and were the coding sequences in exon and the loxP to and Cre of sequences the loxP sites the sequences as as the to this as Cre-mediated and In to ubiquitous of calpain these were with a which Cre the of the to as M. J. P. M. A. P. 1997; PubMed Google Scholar). The derived from the at embryonic Cell were from The and internal were and used for by were with in in for at were with and in with and were used in the were as S.R. H. J. Cell Physiol. PubMed Scopus Google Scholar). were in at a of and maintained at that by were the and were provided by at of The was from and the in using The capn4 was using and at a of the was by cells with and the and as M. D. J. 2003; PubMed Scopus Google Scholar). 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Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of protein was on was activated by the with and its activity was by of the of the with m-calpain cells were with an using or cells were with and by using the green and to and the ER, was using the which was using the were expressed as of at was using with of at and Expression of were from and and calpain activity was by in vitro As expected, μ- and m-calpain activity was in not in the were with a encoding the mouse capn4 both μ- and m-calpain activity were of these cell the of small subunit in we also that steady-state levels of both and m-80 were and this was also by with the capn4 ER with ER and have been reported to ER stress-induced apoptosis by caspase-12 activation (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). is in the cell and is with and it might at and in the in response to as calcium S. S. F. M. A. A. H. P. W. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). been at the with membrane and the of the ER and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In of in the ER with or of the with an in cytoplasmic levels by no was observed and not calpain ER stress, we of fibroblasts with an De T. A. P. Elce J.S. PubMed Scopus Google Scholar). was in the or we observed a in calpain ER as by of and This that calpain was to the ER in with calcium release large subunits have a of are activation D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2305) Google Scholar). therefore the stability of calpain large subunits or as an of their of activation. In m-80 subunit levels or Although was m-80 subunit in that was or The subunit was not as in in we that the subunit also or This of calpain catalytic subunits is with the that are activated and ER to Cell calpain is involved in the ER stress we or apoptosis in with or first used from and to these apoptosis were using and their or for apoptosis was by of cells or and of apoptotic cells cells were in with the in response to either or cells were also observed in the with their capn4 was also by where cells with a of were apoptotic This also that calpain deficiency in either or correlated with resistance to ER stress-induced apoptosis. a role for calpain in ER stress-induced of cells ER cells were by the of cells with a of by and were for with or TN, as and their were for with ER of the plays a role in ER stress-induced apoptosis T. H. N. Li J. Yuan J. Nature. 2000; PubMed Scopus Google Scholar). activation of the cleavage of a caspase-12 directly of release from the (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar, N. K. H. T. Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in activates the to apoptosis. cells were to ER stress-induced apoptosis, and in vitro that m-calpain of into an by cleavage of the N-terminal regulatory (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). therefore ER stress-induced caspase-12 cleavage and activation was in In the caspase-12 was in response to cleavage was in the This was also of In the caspase-12 cleavage was as as and of In contrast, caspase-12 cleavage was in the cells the levels of caspase-12 and this was these a role for calpain in ER stress-induced caspase-12 activation. caspase-12 directly and which in we the requirement for calpain in ER stress-induced activation of and as as cleavage of the In the was activated it and to a in the As expected, cleavage the activation of During activation of the was observed in to In which calpain small subunit and calpain was to the in response to In the a small of was In that been with the capn4 we observed a of and this was as as The of cleavage and activation correlated with of activation in these with cleavage of both and at in with in the cells the of by ER caspase-12 is to be the of ER stress-induced apoptosis, it was that activation of ER residing proteins of caspase-12 because caspase-12 was not in knock-out cells Li C. G. T. Yuan J. Thompson J. Cell Biol. 2003; PubMed Scopus Google Scholar, A. EMBO PubMed Scopus Google Scholar). Although the of activation is a role for proteins been proposed N. K. K. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). suggested that calpain a role in cleaving it was still that calpain at the of activation. been implicated in the of family cleavage apoptosis D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2305) Google Scholar). cleavage of in cells is proposed to an anti-apoptotic molecule into a pro-apoptotic ER stress-induced apoptosis (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). therefore the protein levels of of the family in cells and their capn4 ER stress induced apoptosis we not any in either the state or levels of Bax, Bcl-2, and and S.R. R.A. L.A. J.S. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This suggested that μ- and m-calpain not directly these proteins in cells ER ER of the MAP stress JNK activation activation of JNK activation was in both the and JNK were activated in with of the JNK and the JNK were both in we the kinase, G. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). at the activation which is for the of ASK1, was induced by in not in in the activation of ASK1, JNK, and c-Jun was observed in This in the ER stress was also in where it was using the capn4 calpain as an in the of the ER stress-induced ASK1-JNK major including and were not by calpain deficiency in these to ER of the major to ER stress, including genes encoding the chaperone protein and the transcription and and their capn4 no in or levels or was any in the levels of the alternatively This that calpain not IRE1 activation and its release from the ER because mRNA levels of the ATF6 and the Perk were and their capn4 we that Bip protein levels mRNA were in with the capn4 and was observed the and In this we novel genetic evidence that calpain in the apoptosis response to ER This the proposed of calpain in activation of and it also provides novel evidence calpain in activation of and the JNK stress response Although calpain been implicated in cleavage and of family not a role in the of ER stress in from the conditional capn4 knock-out a powerful in vitro to the functions of The capn4 knock-out lacked any detectable μ- and m-calpain or small subunit and this activity and was with capn4 This genetic model is to which of calpain and which lack or the to completely calpain activity. to calcium in calpain subunits which and to calpain D.E. Thompson V.F. Li H. Wei W. Cong J. Physiol. Rev. 2003; 83: 731-801Crossref PubMed Scopus (2305) Google Scholar). In ER stress calcium from the ER, and this been reported to calpain C. M. K. J. C. EMBO J. 2003; PubMed Scopus Google Scholar, S. P. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, R. G. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). also been suggested that this might calpain to the ER S. S. F. M. A. A. H. P. W. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). was reported to have a wide including the ER and S. S. F. M. A. A. H. P. W. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In or intracellular calcium levels in and this was by accumulation of m-calpain at the ER This suggested that calpain to the ER might be to calcium also that with or correlated with of and m-80 protein levels activated calpain the observed accumulation of calpain at the ER and of large subunits ER stress that calpain is activated at the ER in response to calcium pro-apoptotic role for calpain at the ER was suggested by the that ER stress-induced apoptosis was in and The ER of calpain or might it to including were shown to ER stress-induced caspase-12 and in vitro evidence for cleavage and activation of caspase-12 provided an model to this (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). in compelling genetic to this of calpain correlated with a in or activation of and and cleavage of in response to ER stress, calpain might be activated by calcium it to and caspase-12 might directly of the and that in might directly (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar, N. K. H. T. Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. H. M. G. D.E. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). family are also involved in the ER stress-induced apoptotic response S. Rev. 2002; PubMed Scopus Google Scholar). of to the ER ER stress-induced apoptosis J. C. 2002; PubMed Scopus Google Scholar). the caspase-12 was not and activated in knock-out this cleavage be induced by the of Li C. G. T. Yuan J. Thompson J. Cell Biol. 2003; PubMed Scopus Google Scholar, A. EMBO PubMed Scopus Google Scholar). activation ER stress might of by as J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) or N. K. K. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to the activation of Calpains have also been implicated in cleavage of family including D.E. Thomas A. Devi L.A. Berman Y. Beavis R.C. Reed J.C. Newcomb E.W. Oncogene. 1998; 17: 1069-1078Crossref PubMed Scopus (303) Google Scholar, D.E. Newcomb E.W. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar) and (9Nakagawa T. Yuan J. J. Cell Biol. 2000; 150: 887-894Crossref PubMed Scopus (1029) Google Scholar). This the that activation of caspase-12 might a role for calpain in cleavage of family of a of these proteins to any in their state levels or ER stress-induced levels in the that calpain might as a from activation to caspase-12 activation. ER might calcium release from the ER by the role of on calcium release C. Li C. J. M. Thompson Cell Biol. PubMed Scopus Google Scholar) thus This the of calpains of to in this is that caspase-12 is not involved in it a role in and release M. M. L.A. S. Nature. PubMed Scopus Google Scholar). been implicated in ER stress-induced apoptosis in cells J. T. Y. T. M. Y. T. S. Y. K. Y. M. J. Cell Biol. PubMed Scopus Google Scholar). therefore be to the role of calpain in at the might also be involved in apoptotic that with ER stress-induced cells of in response to the and this was not by ER stress also not any in calpain cells The pathway and the protective are ER stress because activation of the Perk pathway was not in knock-out cells A. EMBO PubMed Scopus Google Scholar). In cells IRE1 and Perk functions based the of Bip and and the observed of alternatively we a in the JNK pathway in cells and this be to a in activation. JNK activation with caspase-12 IRE1 which in activates the cascade. also with caspase-12 and caspase-12 cleavage and activation T. K. K. D. F. T. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). This might also the cleavage of caspase-12 in the cells cells also have a in activation IRE1 activation calpain might of to the ER by it to be the of calpain are which might to activation ER The of activation been in the of stress and G. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) proteins H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. M. K. K. Y. M. K. H. EMBO J. 1998; 17: PubMed Scopus Google protein kinase K. A. H. K. S. J. K. H. EMBO PubMed Scopus Google and H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with roles in regulation, therefore calpain the ER stress response for In using targeted capn4 knock-out we have an pro-apoptotic role for the ubiquitous calpains in the ER stress that calcium release from the ER to the and activation of which is for the activation of and activation of and also novel evidence calpain in the activation of ASK1, and activation of and to be calpain are for activation. and for on and and for of the with

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