Abstract
The X region of the HTLV-I genome contains four major open reading frames (ORFs), two of which, termed x-I and x-II, are of still undefined biological significance. By indirect immunofluorescence and dual labeling with marker proteins, we demonstrate that p13II, an 87-amino acid protein coded by the x-II ORF, is selectively targeted to mitochondria. Mutational analysis revealed that mitochondrial targeting of p13II is directed by an atypical 10-amino acid signal sequence that is not cleaved upon import and is able to target the Green Fluorescent Protein to mitochondria. Expression of p13II results in specific alterations of mitochondrial morphology and distribution from a typical string-like, dispersed network to round-shaped clusters, suggesting that p13II might interfere with processes relying on an intact mitochondrial architecture. Functional studies of mitochondria with the cationic fluorochrome tetramethylrhodamine revealed that a subpopulation of the cells with p13II-positive mitochondria show a disruption in the mitochondrial inner membrane potential (Δψ), an early event observed in cells committed to apoptosis. Taken together, these results suggest novel virus-cell interactions that might be important in HTLV-I replication and/or pathogenicity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Azzone GF and Azzi A. . 1965 Proc. Natl. Acad. Sci. USA 53: 1084–1089.
Bernardi P. . 1992 J. Biol. Chem. 267: 8834–8839.
Bernardi P. . 1999 Physiol. Rev. in press.
Benko DM, Robinson R, Solomin L, Mellini M, Felber BK and Pavlakis GN. . 1990 New Biol. 2: 1111–1122.
Berneman ZN, Gartenhaus RB, Reitz MS, Blattner WA, Manns A, Hanchard B, Ikehara O, Gallo RC and Klotman ME. . 1992 Proc. Natl. Acad. Sci. USA 89: 3005–3009.
Cann AJ and Chen ISY. . 1996 Fields Virology. In: Fields BN, Knipe DM, Howley PM et al. (eds). Human T-cell leukemia virus types I and II Raven Press: New York pp. 1849–1880.
Chen Y-M, Chen S-H, Fu C-Y, Chen J-Y and Osame M. . 1997 Int. J. Cancer 71: 196–202.
Ciminale V, Pavlakis GN, Derse D, Cunningham CP and Felber BK. . 1992 J. Virol. 66: 1737–1745.
Collins ND, Newbound GC, Albrecht B, Beard JL, Ratner L and Lairmore MD. . 1998 Blood 91: 4701–4707.
D'Agostino DM, Ciminale V, Zotti L, Rosato A and Chieco-Bianchi L. . 1997 J. Virol. 71: 75–83.
Derse D, Mikovits J, Polianova M, Felber BK and Ruscetti F. . 1995 J. Virol. 69: 1907–1912.
De Vos K, Goossens V, Boone E, Verkammen D, Vancompernolle K, Vandenabeele P, Haegeman G, Fiers W and Grooten J. . 1998 J. Biol. Chem. 273: 9673–9680.
Dietel M, Herzig I, Reymann A, Brandt I, Schaefer B, Bunge A, Heidebrecht HJ and Seidel A. . 1994 J. Cancer Res. Clin. Oncol. 120: 263–271.
Franchini G, Mulluy JC, Koralnik IJ, Lo Monico A, Sparkowski JJ, Andresson T, Goldstein DJ and Schlegel R. . 1993 J. Virol. 67: 7701–7704.
Franchini G. . 1995 Blood 86: 3619–3639.
Graham FJ and Van der Eb AJ. . 1973 Virology 52: 456–460.
Green DR. . 1998 Cell 94: 695–698.
Henderson S, Huen D, Rowe M, Dawson C, Johnson J and Rickinson A. . 1993 Proc. Natl. Acad. Sci. USA 90: 8479–8483.
Hickish T, Robertson D, Clarke P, Hill M, di Stefano F, Clarke C and Cunningham D. . 1994 Cancer Res. 54: 2808–2811.
Kluck RM, Bossy-Wetzel E, Green DR and Newmeyher DD. . 1997 Science 275: 1132–1136.
Koralnik IJ, Gessain A, Klotman ME, Lo Monico A, Berneman ZN and Franchini G. . 1992 Proc. Natl. Acad. Sci. USA 89: 8813–8817.
Koralnik IJ, Fullen J and Franchini G. . 1993 J. Virol. 67: 2360–2366.
Kroemer G, Zanzami N and Susin SA. . 1997 Immunology Today 18: 44–51.
Kroemer G, Dallaporta B and Resche-Rigon M. . 1998 Ann. Rev. Physiol. 60: 619–642.
Liu X, Kim CN, Yang J, Jemmerson R and Wang X. . 1996 Cell 86: 147–157.
Mermer B, Felber BK, Campbell M and Pavlakis GN. . 1990 Nucleic Acids Res. 18: 2037–2044.
Mulloy JC, Crowley RW, Fullen J, Leonard WJ and Franchini G. . 1996 J. Virol. 70: 3599–3605.
Neupert W. . 1997 Ann. Rev. Biochem. 66: 863–917.
Petronilli V, Miotto G, Canton M, Colonna R, Bernardi P and Di Lisa F. . 1998 BioFactors 8: 263–272.
Prasher DC, Eckenrode VK, Ward WW, Prendgast FG and Cormier MJ. . 1992 Gene 111: 229–233.
Rabson AB and Graves BJ. . 1997 In Coffin JM et al. (ed.). Retroviruses: Synthesis and processing of viral RNA. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York pp. 205–261.
Rizzuto R, Brini M, Pizzo P, Murgia M and Pozzan T. . 1995 Current Biology 5: 635–642.
Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA and Pozzan T. . 1998 Science 280: 1763–1766.
Rojo G, Chamorro M, Salas M, Vinuela E, Cuezva JM and Salas J. . 1998 J. Virol. 72: 7583–7588.
Rost B and Sander C. . 1994 Proteins 19: 55–72.
Schwartz S, Felber BK, Benko DM, Fenyö EM and Pavlakis GN. . 1990 J. Virol. 64: 2519–2529.
Smith DB and Corcoran LM. . 1994 n: Ausubel FM et al. (eds). Current Protocols in Molecular Biology, Volume 2: Expression and purification of glutathione-S-tranferase fusion proteins. John Wiley & Sons: New York. pp. 1671–1677.
Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M and Kroemer G. . 1996 J. Exp. Med. 184: 1331–1341.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G. . 1999 Nature 397: 441–446.
Tollefson AE, Ryerse JS, Scaria A, Hermiston TW and Wold WSM. . 1996 Virology 220: 152–162.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X. . 1997 Science 275: 1129–1132.
Yoshida M. . 1996 Sem. Virol. 7: 349–360.
Acknowledgements
We thank Marta Murgia, Daniela Saggioro and Fabio di Lisa for helpful discussions, Barbara K Felber, George N Pavlakis, Roberto Bisson and Rosario Rizzuto for generously providing plasmids and reagents, and Pierantonio Gallo for preparing the artwork. This study was supported by grants from the Istituto Superiore di Sanita’ (II Progetto AIDS), the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione Italiana per la Ricerca sul Cancro (FIRC). D M D'Agostino was supported by sequential fellowships from the Istituto Superiore di Sanita'-Progetto AIDS and from the FIRC. L Zotti was supported by a fellowship from the Associazione Italiana per la Lotta contro l'AIDS. The Department of Oncology and Surgical Sciences of the University of Padova participated in the concerted action ‘HTLV European Research Network’ (HERN) of the European Commission Biomed Program.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ciminale, V., Zotti, L., D'Agostino, D. et al. 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 (1999). https://doi.org/10.1038/sj.onc.1203047
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203047
Keywords
This article is cited by
-
HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report
BMC Musculoskeletal Disorders (2023)
-
A subpopulation of arenavirus nucleoprotein localizes to mitochondria
Scientific Reports (2021)
-
Silencers of HTLV-1 and HTLV-2: the pX-encoded latency-maintenance factors
Retrovirology (2019)
-
Molecular interactions between mitochondrial membrane proteins and the C-terminal domain of PB1-F2: an in silico approach
Journal of Molecular Modeling (2010)
-
HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches
Apoptosis (2008)