2 †Present address: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, IMM-6, La Jolla, CA 9037, USA.
The VP40 matrix protein of Marburg virus (MARV) has been shown to be the driving force behind MARV budding, a process in which the PPPY L-domain motif of VP40 plays a critical role. Here, we report that Vps4B and Nedd4.1 play critical roles in MARV VP40-mediated budding. We showed that unidentified activities of the Nedd4.1 HECT domain, along with its E3 ubiquitin ligase activity, may be required for MARV budding. Moreover, we showed that the first WW domain of Nedd4.1, WW1, is critical for binding to MARV VP40, indicating that MARV VP40 and Ebola virus VP40 are recognized by a different WW domain of Nedd4.1. This is the first report showing that the viral L-domains containing PPxY have specificities for binding to WW domains. Our findings provide new insights into MARV budding, which may contribute to the development of novel anti-MARV therapeutic strategies.
Anan, T., Nagata, Y., Koga, H., Honda, Y., Yabuki, N., Miyamoto, C., Kuwano, A., Matsuda, I., Endo, F. & other authors(1998). Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes. Genes Cells3, 751–763.[CrossRef][Google Scholar]
Becker, S., Spiess, M. & Klenk, H. D.(1995). The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus. J Gen Virol76, 393–399.[CrossRef][Google Scholar]
Blot, V., Perugi, F., Gay, B., Prevost, M. C., Briant, L., Tangy, F., Abriel, H., Staub, O., Dokhelar, M. C. & Pique, C.(2004). Nedd4.1-mediated ubiquitination and subsequent recruitment of Tsg101 ensure HTLV-1 Gag trafficking towards the multivesicular body pathway prior to virus budding. J Cell Sci117, 2357–2367.[CrossRef][Google Scholar]
Bouamr, F., Melillo, J. A., Wang, M. Q., Nagashima, K., de Los Santos, M., Rein, A. & Goff, S. P.(2003). PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1 Gag and mediates its functional interaction with cellular proteins Nedd4 and Tsg101. J Virol77, 11882–11895.[CrossRef][Google Scholar]
Burleigh, L. M., Calder, L. J., Skehel, J. J. & Steinhauer, D. A.(2005). Influenza a viruses with mutations in the m1 helix six domain display a wide variety of morphological phenotypes. J Virol79, 1262–1270.[CrossRef][Google Scholar]
Chen, B. J. & Lamb, R. A.(2008). Mechanisms for enveloped virus budding: can some viruses do without an ESCRT? Virology372, 221–232.[CrossRef][Google Scholar]
Ciancanelli, M. J. & Basler, C. F.(2006). Mutation of YMYL in the Nipah virus matrix protein abrogates budding and alters subcellular localization. J Virol80, 12070–12078.[CrossRef][Google Scholar]
Dong, X., Li, H., Derdowski, A., Ding, L., Burnett, A., Chen, X., Peters, T. R., Dermody, T. S., Woodruff, E. & other authors(2005). AP-3 directs the intracellular trafficking of HIV-1 Gag and plays a key role in particle assembly. Cell120, 663–674.[CrossRef][Google Scholar]
Garrus, J. E., von Schwedler, U. K., Pornillos, O. W., Morham, S. G., Zavitz, K. H., Wang, H. E., Wettstein, D. A., Stray, K. M., Cote, M. & other authors(2001). Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell107, 55–65.[CrossRef][Google Scholar]
Gosselin-Grenet, A. S., Marq, J. B., Abrami, L., Garcin, D. & Roux, L.(2007). Sendai virus budding in the course of an infection does not require Alix and VPS4A host factors. Virology365, 101–112.[CrossRef][Google Scholar]
Gottlinger, H. G., Dorfman, T., Sodroski, J. G. & Haseltine, W. A.(1991). Effect of mutations affecting the p6 gag protein on human immunodeficiency virus particle release. Proc Natl Acad Sci U S A88, 3195–3199.[CrossRef][Google Scholar]
Gottwein, E., Bodem, J., Muller, B., Schmechel, A., Zentgraf, H. & Krausslich, H. G.(2003). The Mason–Pfizer monkey virus PPPY and PSAP motifs both contribute to virus release. J Virol77, 9474–9485.[CrossRef][Google Scholar]
Harty, R. N., Paragas, J., Sudol, M. & Palese, P.(1999). A proline-rich motif within the matrix protein of vesicular stomatitis virus and rabies virus interacts with WW domains of cellular proteins: implications for viral budding. J Virol73, 2921–2929.
[Google Scholar]
Harty, R. N., Brown, M. E., Wang, G., Huibregtse, J. & Hayes, F. P.(2000). A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding. Proc Natl Acad Sci U S A97, 13871–13876.[CrossRef][Google Scholar]
Heidecker, G., Lloyd, P. A., Fox, K., Nagashima, K. & Derse, D.(2004). Late assembly motifs of human T-cell leukemia virus type 1 and their relative roles in particle release. J Virol78, 6636–6648.[CrossRef][Google Scholar]
Heidecker, G., Lloyd, P. A., Soheilian, F., Nagashima, K. & Derse, D.(2007). The role of WWP1–Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1. J Virol81, 9769–9777.[CrossRef][Google Scholar]
Huang, M., Orenstein, J. M., Martin, M. A. & Freed, E. O.(1995). p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J Virol69, 6810–6818.
[Google Scholar]
Irie, T., Shimazu, Y., Yoshida, T. & Sakaguchi, T.(2007). The YLDL sequence within Sendai virus M protein is critical for budding of virus-like particles and interacts with Alix/AIP1 independently of C protein. J Virol81, 2263–2273.[CrossRef][Google Scholar]
Jasenosky, L. D., Neumann, G., Lukashevich, I. & Kawaoka, Y.(2001). Ebola virus VP40-induced particle formation and association with the lipid bilayer. J Virol75, 5205–5214.[CrossRef][Google Scholar]
Jayakar, H. R., Murti, K. G. & Whitt, M. A.(2000). Mutations in the PPPY motif of vesicular stomatitis virus matrix protein reduce virus budding by inhibiting a late step in virion release. J Virol74, 9818–9827.[CrossRef][Google Scholar]
Kikonyogo, A., Bouamr, F., Vana, M. L., Xiang, Y., Aiyar, A., Carter, C. & Leis, J.(2001). Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells. Proc Natl Acad Sci U S A98, 11199–11204.[CrossRef][Google Scholar]
Kolesnikova, L., Bugany, H., Klenk, H. D. & Becker, S.(2002). VP40, the matrix protein of Marburg virus, is associated with membranes of the late endosomal compartment. J Virol76, 1825–1838.[CrossRef][Google Scholar]
Kolesnikova, L., Bamberg, S., Berghofer, B. & Becker, S.(2004). The matrix protein of Marburg virus is transported to the plasma membrane along cellular membranes: exploiting the retrograde late endosomal pathway. J Virol78, 2382–2393.[CrossRef][Google Scholar]
Kolesnikova, L., Bohil, A. B., Cheney, R. E. & Becker, S.(2007a). Budding of Marburgvirus is associated with filopodia. Cell Microbiol9, 939–951.[CrossRef][Google Scholar]
Kolesnikova, L., Ryabchikova, E., Shestopalov, A. & Becker, S.(2007b). Basolateral budding of Marburg virus: VP40 retargets viral glycoprotein GP to the basolateral surface. J Infect Dis196 (Suppl. 2), S232–S236.[CrossRef][Google Scholar]
Kolesnikova, L., Strecker, T., Morita, E., Zielecki, F., Mittler, E., Crump, C. & Becker, S.(2009). Vacuolar protein sorting pathway contributes to the release of Marburg virus. J Virol83, 2327–2337.[CrossRef][Google Scholar]
Licata, J. M., Simpson-Holley, M., Wright, N. T., Han, Z., Paragas, J. & Harty, R. N.(2003). Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. J Virol77, 1812–1819.[CrossRef][Google Scholar]
Martin-Serrano, J., Zang, T. & Bieniasz, P. D.(2003). Role of ESCRT-I in retroviral budding. J Virol77, 4794–4804.[CrossRef][Google Scholar]
Martin-Serrano, J., Eastman, S. W., Chung, W. & Bieniasz, P. D.(2005). HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway. J Cell Biol168, 89–101.
[Google Scholar]
Parent, L. J., Bennett, R. P., Craven, R. C., Nelle, T. D., Krishna, N. K., Bowzard, J. B., Wilson, C. B., Puffer, B. A., Montelaro, R. C. & Wills, J. W.(1995). Positionally independent and exchangeable late budding functions of the Rous sarcoma virus and human immunodeficiency virus Gag proteins. J Virol69, 5455–5460.
[Google Scholar]
Peters, C. J.(2005). Marburg and Ebola – arming ourselves against the deadly filoviruses. N Engl J Med352, 2571–2573.[CrossRef][Google Scholar]
Plant, P. J., Yeger, H., Staub, O., Howard, P. & Rotin, D.(1997). The C2 domain of the ubiquitin protein ligase Nedd4 mediates Ca2+-dependent plasma membrane localization. J Biol Chem272, 32329–32336.[CrossRef][Google Scholar]
Sakurai, A., Yasuda, J., Takano, H., Tanaka, Y., Hatakeyama, M. & Shida, H.(2004). Regulation of human T-cell leukemia virus type 1 (HTLV-1) budding by ubiquitin ligase Nedd4. Microbes Infect6, 150–156.[CrossRef][Google Scholar]
Schmitt, A. P., Leser, G. P., Morita, E., Sundquist, W. I. & Lamb, R. A.(2005). Evidence for a new viral late-domain core sequence, FPIV, necessary for budding of a paramyxovirus. J Virol79, 2988–2997.[CrossRef][Google Scholar]
Strecker, T., Eichler, R., Meulen, J., Weissenhorn, W., Dieter Klenk, H., Garten, W. & Lenz, O.(2003). Lassa virus Z protein is a matrix protein and sufficient for the release of virus-like particles. J Virol77, 10700–10705.[CrossRef][Google Scholar]
Sudol, M.(1996). Structure and function of the WW domain. Prog Biophys Mol Biol65, 113–132.
[Google Scholar]
Swenson, D. L., Warfield, K. L., Kuehl, K., Larsen, T., Hevey, M. C., Schmaljohn, A., Bavari, S. & Aman, M. J.(2004). Generation of Marburg virus-like particles by co-expression of glycoprotein and matrix protein. FEMS Immunol Med Microbiol40, 27–31.[CrossRef][Google Scholar]
Timmins, J., Schoehn, G., Ricard-Blum, S., Scianimanico, S., Vernet, T., Ruigrok, R. W. & Weissenhorn, W.(2003). Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4. J Mol Biol326, 493–502.[CrossRef][Google Scholar]
Urata, S., Noda, T., Kawaoka, Y., Morikawa, S., Yokosawa, H. & Yasuda, J.(2007a). Interaction of Tsg101 with Marburg virus VP40 depends on the PPPY motif, but not the PT/SAP motif as in the case of Ebola virus, and Tsg101 plays a critical role in the budding of Marburg virus-like particles induced by VP40, NP, and GP. J Virol81, 4895–4899.[CrossRef][Google Scholar]
Urata, S., Yokosawa, H. & Yasuda, J.(2007b). Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix. Virol J4, 66[CrossRef][Google Scholar]
Wills, J. W., Cameron, C. E., Wilson, C. B., Xiang, Y., Bennett, R. P. & Leis, J.(1994). An assembly domain of the Rous sarcoma virus Gag protein required late in budding. J Virol68, 6605–6618.
[Google Scholar]
Yasuda, J. & Hunter, E.(1998). A proline-rich motif (PPPY) in the Gag polyprotein of Mason–Pfizer monkey virus plays a maturation-independent role in virion release. J Virol72, 4095–4103.
[Google Scholar]
Yasuda, J., Hunter, E., Nakao, M. & Shida, H.(2002). Functional involvement of a novel Nedd4-like ubiquitin ligase on retrovirus budding. EMBO Rep3, 636–640.[CrossRef][Google Scholar]
Yasuda, J., Nakao, M., Kawaoka, Y. & Shida, H.(2003). Nedd4 regulates egress of Ebola virus-like particles from host cells. J Virol77, 9987–9992.[CrossRef][Google Scholar]