Abstract
p13II of human T-cell leukemia virus type 1 (HTLV-1) is an 87-amino-acid protein that is targeted to the inner mitochondrial membrane. p13II alters mitochondrial membrane permeability, producing a rapid, membrane potential-dependent influx of K+. These changes result in increased mitochondrial matrix volume and fragmentation and may lead to depolarization and alterations in mitochondrial Ca2+ uptake/retention capacity. At the cellular level, p13II has been found to interfere with cell proliferation and transformation and to promote apoptosis induced by ceramide and Fas ligand. Assays carried out in T cells (the major targets of HTLV-1 infection in vivo) demonstrate that p13II-mediated sensitization to Fas ligand-induced apoptosis can be blocked by an inhibitor of Ras farnesylation, thus implicating Ras signaling as a downstream target of p13II function.
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Abbreviations
- ATLL:
-
adult T-cell leukemia/lymphoma
- CREB:
-
cyclic AMP-responsive element binding protein
- Δψ:
-
inner mitochondrial membrane potential
- FasL:
-
Fas ligand
- FPPS:
-
farnesyl pyrophosphate synthase
- HAM/TSP:
-
HTLV-associated myelopathy/tropical spastic paraparesis
- HTLV-1:
-
human T-cell leukemia virus type 1
- IL-2:
-
interleukin 2
- MTS:
-
mitochondrial targeting sequence
- NLS:
-
nuclear localization signal
- ORF:
-
open reading frame
- PBMC:
-
peripheral blood mononuclear cells
- PTP:
-
permeability transition pore
- REF:
-
rat embryo fibroblasts
- RLM:
-
rat liver mitochondria
- RT-PCR:
-
reverse transcription/polymerase chain reaction
- SDS:
-
sodium dodecyl sulfate
References
Franchini G, Nicot C and Johnson JM (2003) Seizing of T cells by human T-cell leukemia/lymphoma virus type 1. Adv. Cancer Res. 89: 69–132
Matsuoka M (2003) Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene 22: 5131–5140
Seiki M, Hattori S, Hirayama Y and Yoshida M (1983) Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemic cell DNA. Proc. Natl. Acad. Sci. USA 80: 3618–3622
Chou KS, Okayama A, Tachibana N, Lee TH and Essex M (1995) Nucleotide sequence analysis of a full-length human T-cell leukemia virus type I from adult T-cell leukemia cells: a prematurely terminated PX open reading frame II. Int. J. Cancer 60: 701–706
Derse D, Mikovits J, Polianova M, Felber BK and Ruscetti F (1995) Virions released from cells transfected with a molecular clone of human T-cell leukemia virus type I give rise to primary and secondary infections of T cells. J. Virol. 69: 1907–1912
Malik KT, Even J and Karpas A (1988) Molecular cloning and complete nucleotide sequence of an adult T cell leukaemia virus/human T cell leukaemia virus type I (ATLV/HTLV-I) isolate of Caribbean origin: relationship to other members of the ATLV/HTLV-I subgroup. J. Gen. Virol. 68: 1695–1710
Gessain A, Boeri E, Yanagihara R, Gallo RC and Franchini G (1993) Complete nucleotide sequence of a highly divergent human T-cell leukemia (lymphotropic) virus type I (HTLV-I) variant from Melanasia: genetic and phylogenetic relationship to HTLV-I strains from other geographical regions. J. Virol. 67: 1015–1023
Niewiesk S, Daenke S, Parker CE, Taylor G, Weber J, Nightingale S and Bangham CR (1994) The transactivator gene of human T-cell leukemia virus type I is more variable within and between healthy carriers than patients with tropical spastic paraparesis. J. Virol. 68: 6778–6781
Smith RET, Niewiesk S, Booth S, Bangham CRM and Daenke S (1997) Functional conservation of HTLV-1 Rex balances the immune pressure for sequence variation in the Rex gene. Virology 237: 97–403
Green PL and Chen ISY (2001) Human T-cell leukemia virus types 1 and 2 In Fields Virology Knipe D, MaH PM (eds). Philadelphia: Lippincott Williams and Wilkins, pp 1941–1970
Albrecht B and Lairmore MD (2002) Critical role of human T-lymphotropic virus type 1 accessory proteins in viral replication and pathogenesis. Microbiol. Mol. Biol. Rev. 66: 396–406
Barmak K, Harhaj E, Grant C, Alefantis T and Wigdahl B (2003) Human T cell leukemia virus type I-induced disease: pathways to cancer and neurodegeneration. Virology 308: 1–12
Ciminale V, Pavlakis GN, Derse D, Cunningham CP and Felber BK (1992) Complex splicing in the human T-cell leukemia virus (HTLV) family of retroviruses: novel mRNAs and proteins produced by HTLV type I. J. Virol. 66: 1737–1745
Koralnik IJ, Fullen J and Franchini G (1993) The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments. J. Virol. 67: 2360–2366
D'Agostino DM, Ciminale V, Zotti L, Rosato A and Chieco-Bianchi L (1997) The human T-cell lymphotropic virus type 1 Tof protein contains a bipartite nuclear localization signal that is able to functionally replace the amino-terminal domain of Rex. J. Virol. 71: 75–83
Zhang W, Nisbet JW, Bartoe JT, Ding W and Lairmore MD (2000) Human T-lymphotropic virus type 1 p30(II) functions as a transcription factor and differentially modulates CREB-responsive promoters. J. Virol. 74: 11270–11277
Zhang W, Nisbet JW, Albrecht B, Ding W, Kashanchi F, Bartoe JT and Lairmore MD (2001) Human T-lymphotropic virus type 1 p30(II) regulates gene transcription by binding CREB binding protein/p300. J. Virol. 75: 9885–9895
Nicot C, Dundr M, Johnson JM, Fullen JR, Alonzo N, Fukumoto R, Princler GL, Derse D, Misteli T and Franchini G (2004) HTLV-1-encoded p30(II) is a post-transcriptional negative regulator of viral replication. Nat. Med. 10: 197–201
Younis I, Khair L, Dundr M, Lairmore MD, Franchini G and Green PL (2004) Repression of human T-cell leukemia virus type 1 and type 2 replication by a viral mRNA-encoded posttranscriptional regulator. J. Virol. 78: 11077–11083
Koralnik IJ, Gessain A, Klotman ME, Lo Monico A, Berneman ZN and Franchini G (1992) Protein isoforms encoded by the pX region of human T-cell leukemia/lymphotropic virus type I. Proc. Natl. Acad. Sci. USA 89: 8813–8817
Berneman ZN, Gartenhaus RB, Reitz Jr. MS, Blattner WA, Manns A, Hanchard B, Ikehara O, Gallo RC and Klotman ME (1992) Expression of alternatively spliced human T-lymphotropic virus type I pX mRNA in infected cell lines and in primary uncultured cells from patients with adult T-cell leukemia/lymphoma and healthy carriers. Proc. Natl. Acad. Sci. USA 89: 3005–3009
Ciminale V, Zotti L, D'Agostino DM, Ferro T, Casareto L, Franchini G, Bernardi P and Chieco-Bianchi L (1999) Mitochondrial targeting of the p13II protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I). Oncogene 18: 4505–4514
Cereseto A, Berneman Z, Koralnik I, Vaughn J, Franchini G and Klotman ME (1997) Differential expression of alternatively spliced pX mRNAs in HTLV-I-infected cell lines. Leukemia 11: 866–870
Caputo A and Haseltine WA (1992) Reexamination of the coding potential of the HTLV-1 pX region. Virology 188: 618–627
Chen YM, Chen SH, Fu CY, Chen JY and Osame M (1997) Antibody reactivities to tumor-suppressor protein p53 and HTLV-I Tof, Rex and Tax in HTLV-I-infected people with differing clinical status. Int. J. Cancer 71: 196–202
Pique C, Ureta-Vidal A, Gessain A, Chancerel B, Gout O, Tamouza R, Agis F and Dokhelar MC (2000) Evidence for the chronic in vivo production of human T cell leukemia virus type I Rof and Tof proteins from cytotoxic T lymphocytes directed against viral peptides. J. Exp. Med 191: 567–572
Robek MD, Wong FH and Ratner L (1998) Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are dispensable for the immortalization of primary lymphocytes. J. Virol. 72: 4458–4462
Derse D, Mikovits J and Ruscetti F (1997) X-I and X-II open reading frames of HTLV-I are not required for virus replication or for immortalization of primary T-cells in vitro. Virology 237: 123–128
Silverman LR, Phipps AJ, Montgomery A, Ratner L and Lairmore MD (2004) Human T-cell lymphotropic virus type 1 open reading frame II-encoded p30II is required for in vivo replication: evidence of in vivo reversion. J. Virol. 78: 3837–3845
Bartoe JT, Albrecht B, Collins ND, Robek MD, Ratner L, Green PL and Lairmore MD (2000) Functional role of pX open reading frame II of human T-lymphotropic virus type 1 in maintenance of viral loads in vivo. J. Virol. 74: 1094–1100
D'Agostino DM, Ranzato L, Arrigoni G, Cavallari I, Belleudi F, Torrisi MR, Silic-Benussi M, Ferro T, Petronilli V, Marin O, Chieco-Bianchi L, Bernardi P and Ciminale V (2002) Mitochondrial alterations induced by the p13II protein of human T-cell leukemia virus type 1. Critical role of arginine residues. J. Biol. Chem. 277: 34424–34433
Wiedemann N, Frazier AE and Pfanner N (2004) The protein import machinery of mitochondria. J. Biol. Chem. 279: 14473–14476
Stuart R (2002) Insertion of proteins into the inner membrane of mitochondria: the role of the Oxa1 complex. Biochim. Biophys. Acta. 1592: 79–87
Silic-Benussi M, Cavallari I, Zorzan T, Rossi E, Hiraragi H, Rosato A, Horie K, Saggioro D, Lairmore MD, Willems L, Chieco-Bianchi L, D'Agostino DM and Ciminale V (2004) Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1. Proc. Natl. Acad. Sci. USA 101: 6629–6634
Hou X, Foley S, Cueto M and Robinson MA (2000) The human T-cell leukemia virus type I (HTLV-I) X region encoded protein p13(II) interacts with cellular proteins. Virology 277: 127–135
Lefebvre L, Vanderplasschen A, Ciminale V, Heremans H, Dangoisse O, Jauniaux JC, Toussaint JF, Zelnik V, Burny A, Kettmann R and Willems L (2002) Oncoviral bovine leukemia virus G4 and human T-cell leukemia virus type 1 p13(II) accessory proteins interact with farnesyl pyrophosphate synthetase. J. Virol. 76: 1400–1414
Arkin IT (2002) Structural aspects of oligomerization taking place between the transmembrane alpha-helices of bitopic membrane proteins. Biochim. Biophys. Acta 1565: 347–363
Fischer WB and Sansom MS (2002) Viral ion channels: structure and function. Biochim. Biophys. Acta 1561: 27–45
Gonzalez ME and Carrasco L (2003) Viroporins. FEBS Lett. 552: 28–34
Griffin SD, Beales LP, Clarke DS, Worsfold O, Evans SD, Jaeger J, Harris MP and Rowlands DJ (2003) The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett. 535: 34–38
Griffin SD, Harvey R, Clarke DS, Barclay WS, Harris M and Rowlands DJ (2004) A conserved basic loop in hepatitis C virus p7 protein is required for amantadine-sensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. J. Gen. Virol. 85: 451–461
Pavlovic D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB and Zitzmann N (2003) The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc. Natl. Acad. Sci. USA 100: 6104–6108
Piller SC, Ewart GD, Premkumar A, Cox GB and Gage PW (1996) Vpr protein of human immunodeficiency virus type 1 forms cation-selective channels in planar lipid bilayers. Proc. Natl. Acad. Sci. USA 93: 111–115
Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP and Kroemer G (2000) The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J. Exp. Med. 191: 33–46
Boya P, Roumier T, Andreau K, Gonzalez-Polo RA, Zamzami N, Castedo M and Kroemer G (2003) Mitochondrion-targeted apoptosis regulators of viral origin. Biochem. Biophys. Res. Commun. 304: 575–581
Jacotot E, Ferri KF, El Hamel C, Brenner C, Druillennec S, Hoebeke J, Rustin P, Metivier D, Lenoir C, Geuskens M, Vieira HL, Loeffler M, Belzacq AS, Briand JP, Zamzami N, Edelman L, Xie ZH, Reed JC, Roques BP and Kroemer G (2001) Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2. J. Exp. Med. 193: 509–519
Poon B, Grovit-Ferbas K, Stewart SA and Chen IS (1998) Cell cycle arrest by Vpr in HIV-1 virions and insensitivity to antiretroviral agents. Science 281: 266–269
Stewart SA, Poon B, Jowett JB and Chen IS (1997) Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. J. Virol. 71: 5579–5592
Stewart SA, Poon B, Jowett JB, Xie Y and Chen IS (1999) Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells. Proc. Natl. Acad. Sci. USA 96: 12039–12043
Pang S, Kang MK, Kung S, Yu D, Lee A, Poon B, Chen IS, Lindemann B and Park NH (2001) Anticancer effect of a lentiviral vector capable of expressing HIV-1 Vpr. Clin. Cancer Res. 7: 3567–3573
Kino T and Pavlakis GN (2004) Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1. DNA Cell Biol. 23: 193–205
Lefebvre L, Ciminale V, Vanderplasschen A, D'Agostino D, Burny A, Willems L and Kettmann R (2002) Subcellular localization of the bovine leukemia virus R3 and G4 accessory proteins. J. Virol. 76: 7843–7854
Kerkhofs P, Heremans H, Burny A, Kettmann R and Willems L (1998) In vitro and in vivo oncogenic potential of bovine leukemia virus G4 protein. J. Virol. 72: 2554–2559
Willems L, Kerkhofs P, Dequiedt F, Portetelle D, Mammerickx M, Burny A and Kettmann R (1994) Attenuation of bovine leukemia virus by deletion of R3 and G4 open reading frames. Proc. Natl. Acad. Sci. USA 91: 11532–11536
Takada S, Kaneniwa N, Tsuchida N and Koike K (1997) Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells. Oncogene 15: 1895–1901
Shintani Y, Yotsuyanagi H, Moriya K, Fujie H, Tsutsumi T, Kanegae Y, Kimura S, Saito I and Koike K (1999) Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system. J. Gen. Virol. 80: 3257–3265
Rahmani Z, Huh KW, Lasher R and Siddiqui A (2000) Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J. Virol. 74: 2840–2846
Chami M, Ferrari D, Nicotera P, Paterlini-Brechot P and Rizzuto R (2003) Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J. Biol. Chem. 278: 31745–31755
Lee YI, Hwang JM, Im JH, Kim NS, Kim DG, Yu DY, Moon HB and Park SK (2004) Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells. J. Biol. Chem. 279: 15460–15471
D'Agostino DM, Bernardi P, Chieco-Bianchi L and Ciminale V . Adv. Cancer Res. 94, in press
Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tennant BC, Cote PJ, Gerin JL, Purcell RH and Miller RH (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J. Virol. 67: 1218–1226
Raj K, Berguerand S, Southern S, Doorbar J and Beard P (2004) E1^E4 protein of human papillomavirus type 16 associates with mitochondria. J. Virol. 78: 7199–7207
Davy CE, Jackson DJ, Wang Q, Raj K, Masterson PJ, Fenner NF, Southern S, Cuthill S, Millar JB and Doorbar J (2002) Identification of a G(2) arrest domain in the E1^E4 protein of human papillomavirus type 16. J. Virol. 76: 9806–9818
Nakahara T, Nishimura A, Tanaka M, Ueno T, Ishimoto A and Sakai H (2002) Modulation of the cell division cycle by human papillomavirus type 18 E4. J. Virol. 76: 10914–10920
Peh WL, Brandsma JL, Christensen ND, Cladel NM, Wu X and Doorbar J (2004) The viral E4 protein is required for the completion of the cottontail rabbit papillomavirus productive cycle in vivo. J. Virol. 78: 2142–2151
Soriano ME, Nicolosi L and Bernardi P (2004) Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha. J. Biol. Chem. 279: 36803–36808
Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79: 1127–11255
Pacher P and Hajnoczky G (2001) Propagation of the apoptotic signal by mitochondrial waves. EMBO J. 20: 4107–4121
Vieira HL, Haouzi D, El Hamel C, Jacotot E, Belzacq AS, Brenner C and Kroemer G (2000) Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator. Cell Death Differ. 7: 1146–1154
Green DR and Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305: 626–629
Adam D, Heinrich M, Kabelitz D and Schutze S (2002) Ceramide: does it matter for T cells? Trends Immunol. 23: 1–4
Denis GV, Yu Q, Ma P, Deeds L, Faller DV and Chen CY (2003) Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial Ras. J. Biol. Chem. 278: 5775–5785
Fujimura S, Suzumiya J, Yamada Y, Kuroki M and Ono J (2003) Downregulation of Bcl-xL and activation of caspases during retinoic acid-induced apoptosis in an adult T-cell leukemia cell line. Hematol. J. 4: 328–335
Rebollo A, Perez-Sala D and Martinez AC (1999) Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: implications in prevention of apoptosis. Oncogene 18: 4930–4939
Gatza ML, Watt JC and Marriott SJ (2003) Cellular transformation by the HTLV-I Tax protein, a jack-of-all-trades. Oncogene 22: 5141–5149
Willems L, Burny A, Collete D, Dangoisse O, Dequiedt F, Gatot JS, Kerkhofs P, Lefebvre L, Merezak C, Peremans T, Portetelle D, Twizere JC and Kettmann R (2000) Genetic determinants of bovine leukemia virus pathogenesis. AIDS Res. Hum. Retroviruses 16: 1787–1795
Liang PH, Ko TP and Wang AH (2002) Structure, mechanism and function of prenyltransferases. Eur. J. Biochem. 269: 3339–3354
Roskoski Jr. R (2003) Protein prenylation: a pivotal posttranslational process. Biochem. Biophys. Res. Commun. 303: 1–7
Hancock JF (2003) Ras proteins: different signals from different locations. Nat. Rev. Mol. Cell. Biol. 4: 373–384
Hueber AO (2000) CD95: more than just a death factor? Nat. Cell. Biol. 2: 23–25
Hannun YA, Luberto C and Argraves KM (2001) Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry 40: 4893–4903
Levin MC, Rosenblum MK, Fox CH and Jacobson S (2001) Localization of retrovirus in the central nervous system of a patient co-infected with HTLV-1 and HIV with HAM/TSP and HIV-associated dementia. J. Neurovirol. 7: 61–65
Kasai T, Ikeda H, Tomaru U, Yamashita I, Ohya O, Morita K, Wakisaka A, Matsuoka E, Moritoyo T, Hashimoto K, Higuchi I, Izumo S, Osame M and Yoshiki T (1999) A rat model of human T lymphocyte virus type I (HTLV-I) infection: in situ detection of HTLV-I provirus DNA in microglia/macrophages in affected spinal cords of rats with HTLV-I-induced chronic progressive myeloneuropathy. Acta Neuropathol. (Berl.) 97: 107–112
Enns GM (2003) The contribution of mitochondria to common disorders. Mol. Genet. Metab. 80: 11–26
Acknowledgements
We thank Ilaria Cavallari, Luigi Chieco-Bianchi, Daniela Saggioro, Paolo Bernardi, Valeria Petronilli, Oriano Marin and Luc Willems for their advice and collaborations; Tatiana Zorzan and Eliana Scarponi for technical assistance; and Pierantonio Gallo and Andrea Azzalini for preparing artwork. The studies performed in our laboratories were supported by grants from the National Institutes of Health (National Cancer Institute Grant 100730 and Fogarty International Center Grant TW 05705), the Ministero dell'Istruzione, dell'Università e della Ricerca, the Associazione and Fondazione Italiana per la Ricerca sul Cancro and the Istituto Superiore di Sanità AIDS Program.
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D'Agostino, D., Silic-Benussi, M., Hiraragi, H. et al. The human T-cell leukemia virus type 1 p13II protein: effects on mitochondrial function and cell growth. Cell Death Differ 12 (Suppl 1), 905–915 (2005). https://doi.org/10.1038/sj.cdd.4401576
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DOI: https://doi.org/10.1038/sj.cdd.4401576
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