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1 Department of Neuroanatomy (Anatomy III), Kanazawa University Graduate School of Medicine, Kanazawa City, Ishikawa 920-8640, Japan
2 Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Suita City, Osaka, 565-0871, Japan
3 Medical College of Georgia, Augusta, Georgia 30912, USA
4 CREST, JST (Japan Science and Technology), Kawaguchi, Saitama 332-0012, Japan
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Introduction |
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/ß (Tirasophon et al. 1998; Wang et al. 1998) and ATF6 (Yoshida et al. 1998), and UPR target genes include molecular chaperones, folding catalysts in the ER and ERAD molecules. If protein loads in the ER exceed its folding capacity or dome defects in the ER stress response exist, cells tend to die, typically, with apoptotic features (Harding et al. 2001). We cloned a cDNA encoding a ubiquitin-like protein from cultured rat astrocytes exposed to hypoxia and submitted this to the DNA Data Bank of Japan under the name, Stress-associated Ubiquitin (Ub)-like Protein (SUP) (accession number: AB033771). However, there have already been several reports concerning this molecule with different names; (Nomura et al. 1994), methyl methanesulphonate (MMS)-inducible fragment1 (Mif1: van Laar et al. 2000, 2002) and Herp (Kokame et al. 2000, 2001; Sai et al. 2002). Because of the amount of work in the literature under the name Herp, we have employed this name for the current paper.
Herp is an ER-resident membrane protein which has a ubiquitin (Ub)-like domain at its N-terminus. Because of its membrane topology, both the N and C terminus of Herp face the cytosol. It seemed unlikely that Herp acts directly as a molecular chaperone for proteins in the ER lumen (Kokame et al. 2000). Instead, it has been postulated that Herp may function for ERAD (van Laar et al. 2002).
To investigate the role of this molecule in terms of the stress response, we targeted the Herp gene in F9 embryonic carcinoma cells. F9 Herp null cells were more vulnerable to ER stress compared with F9 wild-type cells. The ER stress-induced death in F9 Herp null cells was associated with the stabilization of an endogenous ERAD substrate, aberrant ER stress signalling, structural changes in the ER and caspase activation. The N-terminal region, including the ubiquitin-like domain of Herp, was required for the ER stress resistance in F9 cells.
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Results |
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Cultured rat astrocytes were exposed to hypoxia for 20 h and a differentially expressed amplicon of 528 bp was identified. Northern analysis, using this cDNA as a probe, and total RNA harvested from hypoxic astrocytes, confirmed selective up-regulation, compared with normoxia and led us to clone the full-length cDNA. A rat brain cDNA library was screened and a 1.86-kb cDNA was cloned (GENBANK/EMBL/DDBJ accession number: AB033771). The cDNA encoded a protein of 391 amino acids, which was later found to be identical to (Nomura et al. 1994), Mif1 (van Laar et al. 2000) and Herp (Kokame et al. 2000).
Expression and stability of Herp under stress conditions
Consistent with previous reports, expression of Herp protein was up-regulated in response to ER stress in a variety of cell lines including HeLa cells (Fig. 1A), 293T cells (data not shown) and F9 cells (Fig. 2D), or primary astrocytes (data not shown). The specificity of the anti-Herp antibody was confirmed by pre-absorption of the antibody preparation with the peptide used as an immunogen; appearance of the band corresponding to the molecular weight (Mr) of Herp was prevented (data not shown). The existence of the Ub-like domain at the N-terminus of Herp led us to investigate the stability of Herp protein. After treating HeLa cells (Fig. 1B) or 293T cells (data not shown) with tunicamycin (2 µg/mL), pulse-chase analysis demonstrated more rapid degradation of Herp (half-life:T1/2 < 4 h) than ER molecular chaperones, such as GRP (glucose-regulated protein)-78 and GRP94 (T1/2 > 8 h). Addition of the proteasome inhibitor lactacystin slowed degradation of Herp (Fig. 1B, La). To extend the study of Herp expression in response to stress in vivo, the expression of Herp mRNA was assessed in the rat brain after MCA occlusion. Increased Herp transcripts were observed mainly in the peri-ischaemic penumbral region by in situ hybridization (Fig. 1CI), although neuronal cells displayed the highest levels of transcripts (Fig. 1CII).
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The mouse Herp gene was disrupted by homologous recombination in F9 embryonic carcinoma cells (Fig. 2A). Because F9 cells have three alleles for the Herp gene for unknown reasons, we needed to perform three homologous recombinations to eliminate all wild-type alleles of Herp (Fig. 2B). The Herp-knockout F9 cells lost expression of Herp mRNA (Fig. 2C) and protein (Fig. 2D).
ER stress-induced cell death: effect of Herp gene deletion
To analyse the effect of Herp gene disruption on the cellular stress response, F9 wild-type and Herp null cells were treated with ER stress-inducers, tunicamycin (Tm) or thapsigargin (Tg) for 40 h. In related studies, other stress inducers, staurosporine (St) or H2O2, were incubated with cultures for 12 h. In each case, cell viability was measured by MTT assay (Fig. 3A). F9 Herp null cells showed significantly lower viability, compared with F9 wild-type cells, after tunicamycin treatment (Fig. 3AI). A similar trend was observed following thapsigargin treatment, although the effect was less striking (Fig. 3AII). Consistent with these observations, the cellular response to two other inducers of ER stress, calcium ionophore A23187 [GenBank] or 2-deoxyglucose, also depended on the presence of Herp genes (data not shown). In contrast, deletion of Herp alleles had no effect on cell viability following exposure to staurosporine (Fig. 3AIII) or H2O2 (Fig. 3AIV). To distinguish ER stress-induced growth arrest from ER stress-induced cell death, LIVE/DEAD cell toxicity assay was performed after tunicamycin (1 µg/mL; Fig. 3B) or thapsigargin (0.3 µM; data not shown) treatment for 36 h. Nulear staining of dead cells, typically with fragmented structures, was readily apparent in cultures of Herp null cells (Fig. 3BII), while the majority of F9 wild-type cells were intact (Fig. 3BI). Treatment of Herp null cells with cycloheximide (1 µg/mL), a general protein synthesis inhibitor that decreases protein loading in the ER, almost completely rescued these cells from ER stress-induced cell death (Fig. 2BIII). In our system, 1 µg/mL of cycloheximide blocks approximately 75% of protein synthesis (Hori et al. 1994). In contrast, treatment of Herp null cells with lactacystin (1 µM), a potent proteasome inhibitor, accelerated ER stress-induced cell death (Fig. 3BIV). No nuclear staining of dead cells was observed in F9 Herp null cells under normal conditions (data not shown).
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To assess the proximal events underlying ER stress-induced death in F9 Herp null cells, ER stress signalling was analysed in F9 wild-type and Herp null cells. When cultures were exposed to tunicamycin or thapsigargin for 6 h, GRP78 and CHOP transcripts, which are downstream targets of UPR and translation suppression, respectively, showed a somewhat greater degree of up-regulation in F9 Herp null cells than in F9 wild-type cells (Fig. 6A). The time-course studies in which F9 cells were treated with tunicamycin (2 µg/mL) revealed that, early in the incubation period (5–8 h), enhanced expressions of GRP78 and CHOP (Zinszner et al. 1998) mRNA were more readily detected in F9 Herp null cells compared with F9 wild-type cells. In contrast, later in the tunicamycin-treated period (12–21 h), the expressions of GRP78 and CHOP transcripts were evident in F9 wild-type cells compared with F9 Herp null cells (Fig. 6B). At the protein level, increased expressions (Fig. 6C) or activation (Fig. 6D) of the downstream targets of the ER stress signalling pathways, such as GRP 78, GRP 94, XBP1 (Yoshida et al. 2001; Calfon et al. 2002), CHOP and JNK (Urano et al. 2000), were detected at higher levels in F9 Herp null cells than F9 wild-type cells, following exposure to ER stress-inducers for 8 h.
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Ectopic expression of Herp cDNA rescues F9 Herp null cells from enhanced vulnerability to ER stress
To be certain that disruption of the Herp gene was responsible for the susceptibility of Herp null cells to ER stress, rescue experiments were performed by over-expressing Herp cDNAs. In order to accomplish this, full-length (FL-Herp) or N-terminus truncated (dN-Herp) rat Herp cDNA in Hpch(+) was constructed and transfected into F9 Herp null cells. Hpch(+) was a plasmid with Herp promoter and hygromycin resistance gene, and generated as described in Experimental procedures. Two clones stably expressing full-length Herp protein (FL-Herp 1, 2) and three clones stably expressing N-terminus truncated Herp protein (dN-Herp 1, 2, 3) were obtained after selecting cells with hygromycin. The levels of expression of Herp antigen in control and tunicamycin-treated conditions, assessed by Western blotting with anti-Herp or anti-FLAG antibody, were compared with those of F9 wild-type cells (Wt) (Fig. 7A,B). As anti-Herp antibody recognizes the Ub-like domain of Herp, dN-Herp protein was only detected by anti-FLAG antibody. Subcellular fractionation studies followed by Western blotting with anti-Herp or with anti-FLAG antibody revealed that both endogenous and ectopically expressed Herp were localized in the ER and, probably to a lesser extent, in Golgi apparatus (data not shown). When cells were exposed to tunicamycin for the indicated times, FL-Herp, but not dN-Herp, rescued F9 Herp null cells with respect to the levels of Herp antigen (Fig. 7A,B), and in terms of cell viability (Fig. 7C), and caspase 3 activation (Fig. 7D).
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Discussion |
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Targeted disruption of the Herp gene caused F9 embryonic carcinoma cells to become vulnerable to ER stress. The response of F9 Herp null cells to tunicamycin treatment can be divided into three phases, in order to contrast them with F9 wild-type cells. The first or early period (0–8 h after tunicamycin treatment) included enhanced ER stress signalling and stabilization of an ERAD substrate, in F9 Herp null cells compared with F9 wild-type cells (Fig. 6A,C,D,E,F). If tunicamycin was removed during this period, F9 Herp null cells were rescued and downstream events were prevented (Fig. 6G,H). As we also found that cycloheximide treatment prevented the ER stress-induced death in F9 Herp null cells (Fig. 3BIII), while lactacystin treatment accelerated it (Fig. 3BIV), it is likely that unfolded proteins accumulate to a greater degree in F9 Herp null cells, than in wild-type cells, and F9 Herp null cells compensate by increasing folding capacities in the ER in this early period. The second or intermediate stage (8–20 h after tunicamycin treatment) was characterized by reduced ER stress signalling. Transcripts of both GRP78 and CHOP were reduced in F9 Herp null cells during this period (Fig. 6B). In this context, reduced expression of chaperones has been linked to ER stress-induced cell death (Katayama et al. 1999). Once F9 Herp null cells passed into the later or final period (20–40 h after tunicamycin treatment), apoptotic cell death occurred: caspase activation (Fig. 5), structural alteration of the ER (Fig. 4B,F) and chromatin condensation/nuclear fragmentation (Fig. 4C,D). These death-linked events were irreversible, as removal of tunicamycin at this later time did not rescue the cells.
Transfection of Herp cDNAs into F9 Herp null cells revealed that the N-terminal region, including the Ub-like domain of Herp, was required for the ER stress resistance in F9 cells. This also raises the possibility that Herp may function for ERAD and recruit the proteasome complex to the ER with its Ub-like domain, as recently hypothesized (van Laar et al. 2002).
However, Herp has another aspect as an ATF6-dependent gene. Recent reports have attempted to classify ER stress-related genes. One group of such stress-related genes consists of ER-resident molecular chaperones and folding enzymes directly regulated by ATF6 (Okada et al. 2002; Yoshida et al. 2003). EDEM, a gene primarily involved in ERAD (Hosokawa et al. 2001), has been reported to be induced by ER stress, but its up-regulation occurred after those of folding factors whose expressions were under control of ATF6 (Yoshida et al. 2003). Our preliminary results revealed that EDEM was induced within 8 h after tunicamycin treatment in F9 cells (determined by Northern blotting using EDEM cDNA: a gift from Dr N. Hosokawa, Kyoto University), while Herp and GRP78 were both induced within 4 h after tunicamycin treatment, suggesting that Herp may function for some folding processes and enhances general folding capacities in the ER. In this context, it was recently reported that Herp binds to full-length presenilins and enhances production of amyloid beta peptide (Sai et al. 2002). As over-expression of Herp did not alter the steady-state levels of either full-length presenilins or their N-terminal fragments, it is not likely that Herp enhances proteolysis of presenilins.
While further studies will be required to disclose the entire function of Herp, our results emphasize the important role of Herp in the ER stress response.
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Experimental procedures |
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Astrocytes were isolated from the cerebral cortex of E18 Wistar rat embryos and cultured in MEM with 10% FCS as described before (Yamaguchi et al. 1999). 293T cells (a gift from Dr K. Imaizumi, Nara Institute of Science and Technology), HeLa cells and F9 embryonic carcinoma cells (a gift from Drs K. Ohishi and T. Kinoshita, Osaka University) were maintained in DMEM with 10% FCS. Hypoxic stress was created by incubating cells in a chamber (Coy Laboratory Products, Ann Arbor, MI) as previously described (Hori et al. 2002). Other stresses were induced by treating cells with tunicamycin (0.5–2 µg/mL; Sigma, St Louis, MO), thapsigargin (0.1–0.3 µM; Sigma), A23187 [GenBank] (1 µM; Sigma), 2-deoxyglucose (25 mM; Sigma), staurosporine (0.5–2 µM; Sigma), H2O2 (Nakalai Tesque, Kyoto, Japan), cycloheximide (1–2 µg/mL; Sigma) or lactacystin (1–5 µM; Calbiochem, La Jolla, CA) for the indicated times. In some experiments, stress was terminated by washing cells with drug(s)-free medium three times and cells were further incubated for the indicated times.
Differential display and cloning of rat Herp cDNA
Differential display was performed as described before (Yamaguchi et al. 1999). Differential expression of candidate genes in hypoxia vs. normoxia was confirmed by Northern blotting using 32P-radiolabelled cDNAs as probes. Several ER stress-inducible genes including GRP78, GRP94 and calreticulin were obtained, and one of the cDNA fragments from unknown genes was used to screen an adult cDNA library (lambda ZapII cDNA library, Stratagene, La Jolla, CA).
Northern blot analysis
Total RNA (10 µg), isolated from cultured astrocytes, HeLa cells and F9 cells was separated on agarose/formaldehyde (1%) gels and transferred onto nylon membranes. cDNA fragments for probes were generated as follows. Herp cDNA was obtained as described above. Rat GRP78 and ß-actin cDNAs were cloned by PCR with specific primers. CHOP cDNA was kindly provided by Dr D. Ron (New York University, USA). Each fragment was labelled with 32P-dCTP by the random hexamer procedure (Yamaguchi et al. 1999).
Plasmid construction, transfection and generation of antibodies
Rat Herp cDNA encoding the complete open reading frame was amplified by PCR using primers tagged with FLAG epitope at the N-terminus and cloned into Hpch(+). Hpch(+) vector was generated by replacing CMV promoter of pcDNA3.1(+) hygro (Invitrogen) with proximal 517 bp of mouse Herp promoter which includes both ERSE and ERSE II. Rat Herp cDNA lacking N-terminus (residues 1–97) was also developed by PCR using FLAG tagged primers at the N-terminus and cloned into Hpch(+). All constructs were sequenced prior to transfection studies. Transfection was performed into F9 cells by electroporation (25 µg DNA/107 cells). To obtain antibodies reactive with Herp, a peptide derived from its Ub-like domain with the sequence KSPNQRHRDLELSGDRG (residues 15–31) was synthesized and conjugated to keyhole limpet haemocyanin. Rabbits were immunized by conventional methods and, once high titre antibodies were obtained, the antisera were purified by protein G column (Invitrogen).
Cell lysis, subcellular fractionation and Western blotting
Cultured astrocytes, HeLa cells, F9 cells or 293T cells (5 x 106 cells) were lysed in buffer containing 10 mM Tris-HCl, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.1% SDS, 0.2% deoxycholate, 1 mM PMSF, 1 µg/mL aprotinin, 1 µg/mL leupeptin and 1 µg/mL pepstatin. Western blotting was then performed using anti-Herp, anti-FLAG (Sigma), anti-KDEL (Stressgen Biotechnologies Corp., Victoria, BC, Canada), anti-CHOP (Santa Cruz Biotechnology, Santa Cruz, CA), anti-caspase 9 (Cell Signalling Technology, Beverly, MA), anti-caspase 12 or anti-XBP1 antibody (the latter two antibodies were gifts from Dr D. Ron, New York University). Sites of primary antibody binding were determined by alkaline phosphatase-conjugated secondary antibodies.
Metabolic labelling and pulse-chase analysis
HeLa cells, 293T cells (5 x 106 cells/condition) or F9 cells either with or without exposure to tunicamycin for the indicated times, were labelled with 35S-methionine (200 µCi/mL; Amersham Pharmacia Biotech, Piscataway, NJ) for 30 min in methionine-free DMEM with 10% dialysed FCS and chased for the indicated times (up to 16 h) in regular medium. In some experiments, cells were continuously labelled for 3 h with 35S-methionine. Cell extracts (see above) were immunoprecipitated with anti-Herp, anti-KDEL or anti-connexin 43 antibody (Santa Cruz Biotechnology) for 12 h at 4 °C and subjected to SDS–PAGE followed by autoradiography.
In situ hybridization
Unilateral middle cerebral artery (MCA) occlusion was performed in male Sprague-Dawley rats (250 g) as previously described (Yamaguchi et al. 1999). After 8-h ischaemia, the rats were killed and brains were frozen at –80 °C. Serial coronal sections were cut and the distribution of Herp mRNA was examined by in situ hybridization using previously described techniques (Yamaguchi et al. 1999). In brief, sense and anti-sense riboprobes for Herp were in vitro transcribed from the rat Herp cDNA inserted into the pGEM T vector. After linearizing the vector with NcoI (for the sense probe) or SpeI (for the anti-sense probe), reaction mixtures were incubated with 35S-UTP (NEG-039H, Dupont NEN; Wilmington, DE) and SP6 or T7 RNA polymerase (Promega, Madison, WI). Brain sections were then hybridized with either sense or anti-sense probes and washed, dried and subjected to autoradiography. Two days later, films were developed and brain images were examined. For some sections, slides were covered with photographic emulsion (Kodak, NY) for 2 weeks and were then developed and analysed by dark-field microscopy.
Establishment of Herp-knockout F9 embryonic carcinoma cells
Herp null F9 cells were prepared as previously described (Ohishi et al. 2000). Briefly, a targeting vector was constructed in pPNT (a gift from Dr Tybulewicz, MRC National Institute for Medical Research, London, UK) by replacing exon 1 of the mouse Herp gene derived from 129Sv/J library (Incyte Genomics, St Louis, MO) with PGK-neo, PGK-puro or PGK-zeo cassette (Fig. 3A). F9 cells were electroporated with targeting plasmids linearized with NotI or SwaI (25 µg DNA/107 cells) and selected with appropriate drugs. Concentrations of G418 (Sigma), puromycin (Sigma) and Zeocin (Invitrogen) were 400, 2 and 500 µg/mL, respectively. Recombinants were screened by PCR and confirmed by Southern blotting with 5'- and 3'-probes after digesting DNA with Kpn1 (Fig. 3B). For rescue experiments, F9 Herp null cells were electroporated with rat Herp cDNA/Hpch(+) and selected with hygromycin (Sigma) at 350 µg/mL.
Measurement of cell viability, caspase activities and JNK activity
After cells were treated with the indicated reagents, cell viability was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay (Chemicon, Temecula, CA) or with LIVE/DEAD cell toxicity kit (Molecular Probes, Eugene, OR). Caspase activities were measured by substrate cleavage (caspase 2, 3, 6 and 8-like activities; Chemicon), by Western blotting (caspase 9 and 12) or by immunostaining with activated-caspase 3 antibody (Promega). The substrates used were DEVD-p-nitroanilide (pNA; caspase 3), VDVAD-pNA (caspase 2), VEID-pNA (caspase 6) and IETD-pNA (caspase 8). JNK activity was measured using SAPK/JNK Assay kit (Cell Signalling Technology).
Electron microscopic analysis
Electron microscopic analysis was performed as described before (Miyoshi et al. 2000). Briefly, F9 wild-type cells or Herp null cells were treated with tunicamycin (1 µg/mL) for the indicated times and fixed in PBS containing 4% paraformaldehyde and 2% glutaraldehyde. They were post fixed with OsO4 at 25 °C for 30 min, dehydrated in graded ethanol solutions and embeded in Quetol 812 (Nisshin EM Co.). Sections (80 nm) were cut, stained with uranyl acetate (10% in 50% ethanol) and lead citrate and then examined with a Hitachi H-7100 electron microscope.
Laser densitometric analysis and statistical analysis
Laser densitometric analysis was performed to standardize the results of Western and Northern blotting with NIH Image software. Statistical analysis was performed with Student's t-test.
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Acknowledgements |
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* Correspondence: Email: osamuh{at}nanat.m.kanazawa-u.ac.jp
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References |
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Received: 4 January 2004
Accepted: 11 February 2004
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 S. Tuvia, D. Taglicht, O. Erez, I. Alroy, I. Alchanati, V. Bicoviski, M. Dori-Bachash, D. Ben-Avraham, and Y. Reiss The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp J. Cell Biol., April 9, 2007; 177(1): 51 - 61. [Abstract] [Full Text] [PDF]
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K. Takano, Y. Tabata, Y. Kitao, R. Murakami, H. Suzuki, M. Yamada, M. Iinuma, Y. Yoneda, S. Ogawa, and O. Hori Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin Am J Physiol Cell Physiol, January 1, 2007; 292(1): C353 - C361. [Abstract] [Full Text] [PDF]
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 G. Liang, T. E. Audas, Y. Li, G. P. Cockram, J. D. Dean, A. C. Martyn, K. Kokame, and R. Lu Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element Mol. Cell. Biol., November 1, 2006; 26(21): 7999 - 8010. [Abstract] [Full Text] [PDF]
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 C. Wojcik, M. Rowicka, A. Kudlicki, D. Nowis, E. McConnell, M. Kujawa, and G. N. DeMartino Valosin-containing Protein (p97) Is a Regulator of Endoplasmic Reticulum Stress and of the Degradation of N-End Rule and Ubiquitin-Fusion Degradation Pathway Substrates in Mammalian Cells Mol. Biol. Cell, November 1, 2006; 17(11): 4606 - 4618. [Abstract] [Full Text] [PDF]
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O. Hori, M. Miyazaki, T. Tamatani, K. Ozawa, K. Takano, M. Okabe, M. Ikawa, E. Hartmann, P. Mai, D. M. Stern, et al. Deletion of SERP1/RAMP4, a Component of the Endoplasmic Reticulum (ER) Translocation Sites, Leads to ER Stress. Mol. Cell. Biol., June 1, 2006; 26(11): 4257 - 4267. [Abstract] [Full Text] [PDF]
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