Abstract
The Moloney murine leukemia virus (MoMuLV)-ts1 retrovirus, a naturally occurring mutant of MoMuLV-TB, causes a neuroimmunodegenerative syndrome in mice. The authors show here that ts1 triggers apoptosis in immortalized astrocytes, C1 cells, and primary cultured astrocytes, and that this apoptosis is caused by endoplasmic reticulum (ER) stress resulting from accumulation of the viral envelope preprotein gPr80env. In ts1-infected C1 cells, an unfolded protein response was identified by activation of the ER-resident transmembrane protein kinase PERK, an event that leads to hyperphosphorylation of eIF2α, up-regulation of GRP78, increased amounts of GADD153/CHOP, and cleavage of procaspase-12. Up-regulation of GRP78 and cleavage of procaspase-12 were also detected in primary cultured astrocytes infected with ts1. In ts1-infected C1 cells, ER stress was followed by mitochondrial stress, detected as mitochondrial transmembrane potential dissipation, cleavage of procaspase-9, and induction of activated caspase-3. In the brain-stems of ts1-infected mice, activated caspase-3 and damaged mitochondria were identified in astrocytes within areas showing spongiform degeneration. Together the data imply that both ER stress- and mitochondrial stress-related apoptotic pathways are involved in ts1-induced astrocyte death.
Similar content being viewed by others
References
Aridor M, Hannan LA (2000). Traffic jam: a compendium of human diseases that affect intracellular transport processes. Traffic 1: 836–851.
Atwood WJ, Berger JR, Kaderman R, Tornatore CS, Major EO (1993). Human immunodeficiency virus type 1 infection of the brain, Clin Microbiol Rev 6: 339–366.
Baeuerle PA, Baichwal VR (1997). NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 65: 111–137.
Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000). Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2: 326–332.
Brack-Werner R (1999). Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13: 1–22.
Clark S, Duggan J, Chakraborty J (2001). Ts1 and LP-BM5: a comparison of two murine retrovirus models for HIV. Viral Immunol 14: 95–109.
Crise B, Buonocore L, Rose JK (1990). CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J Virol 64: 5585–5593.
Crise B, Rose JK (1992). Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum. J Virol 66: 2296–2301.
Choe W, Stoica G, Lynn W, Wong PKY (1998). Neurodegeneration induced by MoMuLV-ts1 and increased expression of Fas and TNF-alpha in the central nervous system. Brain Res 779: 1–8.
Danbolt NC (2001). Glutamate uptake. Prog Neurobiol 65: 1–105.
Diedrich JF, Bendheim PE, Kim YS, Carp RI, Haase AT (1991). Scrapie associated prion protein accumulates in astrocytes during scrapie infection. Proc Natl Acad Sci USA 88: 375–379.
Dimcheff DE, Askovic S, Baker AH, Johnson-Fowler C, Portis JL (2003). Endoplasmic reticulum stress is a determinant of retrovirus-induced spongiform neurodegeneration. J Virol 77: 12617–12629.
Duchen MR (2000). Mitochondria and calcium: from cell signalling to cell death. J Physiol 529(Pt 1): 57–68.
Friedlander RM (2003). Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348: 1365–1375.
Galey D, Becker K, Haughey N, Kalehua A, Taub D, Woodward J, Mattson MP, Nath A (2003). Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes. J NeuroVirol 9: 358–371.
Gonzales-Scarano F, Nathanson N, Wong PKY (1995). Retroviruses and the nervous system. In: The Retroviridae, vol. 4. Levy JA (ed). New York: Plenum Press, pp 409–490.
Ghorpade A, Holter S, Borgmann K, Persidsky R, Wu L (2003). HIV-1 and IL-1 beta regulate Fas ligand expression in human astrocytes through the NF-kappa B pathway. J Neuroimmunol 141: 141–149.
Hacki J, Egger L, Monney L, Conus S, Rosse T, Fellay I, Borner C (2000). Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19: 2286–2295.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000). Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897–904.
Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C (2003). Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22: 5435–5445.
Hori O, Ichinoda F, Tamatani T, Yamaguchi A, Sato N, Ozawa K, Kitao Y, Miyazaki M, Harding HP, Ron D, Tohyama M, Stern DM, Ogawa S (2002). Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Biol 157: 1151–1160.
Imaizumi K, Miyoshi K, Katayama T, Yoneda T, Taniguchi M, Kudo T, Tohyama M (2001). The unfolded protein response and Alzheimer’s disease. Biochem Biophys Acta 1536: 85–96.
Jacobson J, Duchen MR (2002). Mitochondrial oxidative stress and cell death in astrocytes—requirement for stored Ca2+ and sustained opening of the permeability transition pore. J Cell Sci 115: 1175–1188.
Jordan R, Wang L, Graczyk TM, Block TM, Romano PR (2002). Replication of a cytopathic strain of bovine viral diarrhea virus activates PERK and induces endoplasmic reticulum stress-mediated apoptosis of MDBK cells. J Virol 76: 9588–9599.
Kaul M, Garden GA, Lipton SA (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988–994.
Kim HT, Qiang W, Wong PKY, Stoica G (2001). Enhanced proteolysis of IkappaBalpha and IkappaBbeta proteins in astrocytes by Moloney murine leukemia virus (MoMuLV)-ts1 infection: a potential mechanism of NF-kappaB activation. J NeuroVirol 7: 466–475.
Kim HT, Stoica G, Bazer FW, Ott TL (2000). Interferon tauinduced hepatocyte apoptosis in sheep. Hepatology 31: 1275–1284.
Koga Y, Sasaki M, Nakamura K, Kimura G, Nomoto K (1990). Intracellular distribution of the envelope glycoprotein of human immunodeficiency virus and its role in the production of cytopathic effect in CD4+ and CD4− human cell lines. J Virol 64: 4661–4671.
Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J (1988). The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332: 462–464.
Kroemer G, Reed JC (2000). Mitochondrial control of cell death. Nat Med 6: 513–519.
Kudo T, Katayama T, Imaizumi K, Yasuda Y, Yatera M, Okochi M, Tohyama M, Takeda M (2002). The unfolded protein response is involved in the pathology of Alzheimer’s disease. Ann N Y Acad Sci 977: 349–355.
Land A, Zonneveld D, Braakman I (2003). Folding of HIV-1 envelope glycoprotein involves extensive isomerization of disulfide bonds and conformation-dependent leader peptide cleavage. FASEB J 17: 1058–1067.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479–489.
Lin YC, Chow CW, Yuen PH, Wong PKY (1997). Establishment and characterization of conditionally immortalized astrocytes to study their interaction with ts1, a neuropathogenic mutant of Moloney murine leukemia virus. J NeuroVirol 3: 28–37.
Liu N, Qiang W, Kuang X, Thuillier P, Lynn WS, Wong PKY (2002). The peroxisome proliferator phenylbutyric acid (PBA) protects astrocytes from ts1 MoMuLV-induced oxidative cell death. J NeuroVirol 8: 318–325.
May MJ, Ghosh S (1998). Signal transduction through NF-kappa B. Immunol Today 19: 80–88.
McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001). Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21: 1249–1259.
Micoud F, Mandrand B, Malcus-Vocanson C (2001). Comparison of several techniques for the detection of apoptotic astrocytes in vitro. Cell Prolif 34: 99–113.
Mourelatos Z, Hirano A, Rosenquist AC, Gonatas NK (1994). Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis (ALS). Clinical studies in ALS of Guam and experimental studies in deafferented neurons and in beta,beta′-iminodipropionitrile axonopathy. Am J Pathol 144: 1288–1300.
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403: 98–103.
Nakamura K, Bossy-Wetzel E, Burns K, Fadel MP, Lozyk M, Goping IS, Opas M, Bleackley RC, Green DR, Michalak M (2000). Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis. J Cell Biol 150: 731–740.
Pahl HL, Baeuerle PA (1996). Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett 392: 129–136.
Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby LM, Ellerby HM, Bredesen DE (2001). Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 276: 33869–33874.
Shamu CE, Walter P (1996). Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 15: 3028–3039.
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003). Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23: 3394–3406.
Shikova E, Lin YC, Saha K, Brooks BR, Wong PKY (1993). Correlation of specific virus-astrocyte interactions and cytopathic effects induced by ts1, a neurovirulent mutant of Moloney murine leukemia virus. J Virol 67: 1137–1147.
Siklos L, Engelhardt JI, Reaume AG, Scott RW, Adalbert R, Obal I, Appel SH (2000). Altered calcium homeostasis in spinal motoneurons but not in oculomotor neurons of SOD-1 knockout mice. Acta Neuropathol (Berl) 99: 517–524.
Stoica G, Illanes O, Tasca SI, Wong PKY (1993). Temporal central and peripheral nervous system changes induced by a paralytogenic mutant of Moloney murine leukemia virus TB. Lab Invest 69: 724–735.
Stoica G, Tasca SI, Wong PKY (2000). Motor neuronal loss and neurofilament-ubiquitin alteration in MoMuLV-ts1 encephalopathy. Acta Neuropathol (Berl) 99: 238–244.
Su HL, Liao CL, Lin YL (2002). Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol 76: 4162–4171.
Szurek PF, Yuen PH, Ball JK, Wong PKY (1990). A Val-25-to-Ile substitution in the envelope precursor polyprotein, gPr80env, is responsible for the temperature sensitivity, inefficient processing of gPr80env, and neurovirulence of ts1, a mutant of Moloney murine leukemia virus TB. J Virol 64: 467–475.
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000). Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664–666.
Waris G, Tardif KD, Siddiqui A (2002). Endoplasmic reticulum (ER) stress hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. Biochem Pharmacol 64: 1425–1430.
Wong PKY, Lynn WS (1997). Neuroimmunodegeneration. EOS J Immunol Immunopharmacol 17: 30–35.
Wong PKY, Lynn WS, Lin YC, Choe W, Yuen PH (1998). ts1 MoMuLV: A murine model of neuroimmunodegeneration. In: Neuroimmunodegeneration. Wong PKY, Lynn WS (eds). Heidelberg: R.G. Landes, pp 75–93.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001). XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881–891.
Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K (2000). ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 20: 6755–6767.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by NIH grants AI28283, NS43984, NCI Cancer Center Support grant (CA16672), and NIEHS Center grant (ES07784).
Rights and permissions
About this article
Cite this article
Liu, N., Kuang, X., Kim, HT. et al. Possible involvement of both endoplasmic reticulum- and mitochondria-dependent pathways in MoMuLV-ts1-induced apoptosis in astrocytes. Journal of NeuroVirology 10, 189–198 (2004). https://doi.org/10.1080/13550280490448043
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1080/13550280490448043