Editorial: Role of lipids in virus assembly
- 1Saad Lab, Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
- 2Centre D'études D'agents Pathogènes et Biotechnologies Pour la Santé, Montpellier, France
Viruses utilize cellular lipids during critical steps of replication like entry, assembly, and egress. Growing evidence indicate important roles for lipids and lipid nanodomains in virus assembly. This special topic covers key aspects of virus-membrane interactions during assembly and egress of two classes, retroviruses and filoviruses. It discusses molecular mechanisms of assembly and budding of retroviruses and Ebola virus (EBOV) and how various membrane components facilitate these events. It is well established that assembly of most of retroviral Gag proteins occurs on the plasma membrane (PM) (Ono et al., 2004; Grigorov et al., 2006; Jouvenet et al., 2006, 2008; Finzi et al., 2007; Welsch et al., 2007; Chukkapalli et al., 2008, 2010; Chu et al., 2010; Hamard-Peron et al., 2010; Chukkapalli and Ono, 2011). Biochemical, in vivo, in vitro, and genetic data have identified factors that modulate retroviral Gag-membrane interactions. Studies over the last decade have provided insights on the molecular and structural determinants of Gag-membrane binding. The human immunodeficiency virus type-1 (HIV-1) Gag polyprotein adopts a compact “folded over” conformation and exists in the monomeric or low-order oligomeric states prior to targeting to the PM (Datta et al., 2007, 2011; Kutluay and Bieniasz, 2010; Kutluay et al., 2014). Although, it is established that the nucleocapsid (NC) domain of Gag recognizes motifs in the viral RNA genome to mediate packaging, there is compelling evidence that the matrix (MA) domain also binds to cellular RNA to prevent premature Gag targeting to intracellular membranes (Chukkapalli et al., 2010, 2013; Chukkapalli and Ono, 2011; Hogue et al., 2012; Inlora et al., 2014; Kutluay et al., 2014; Olety and Ono, 2014). Upon transport of Gag to the PM, the interaction of MA with RNA is exchanged for an interaction of MA with PM lipids, inducing an extended conformation of Gag and formation of high-order Gag oligomers on the PM. The key to understanding this essential switch is elucidating at the molecular level the interaction of MA with specific PM components. Several retroviruses like Rous sarcoma virus (RSV), equine infectious anemia virus (EIAV), Mason-Pfizer monkey virus (M-PMV), and human T-lymphotropic virus type (HTLV-1) have evolved distinct mechanisms for Gag membrane targeting and assembly. Our understanding of retroviral Gag-PM interaction is incomplete because of the lack of molecular details on how membrane components contribute to the overall membrane binding. Eight out of the nine articles discuss the latest understanding of retroviral Gag-membrane binding. Prchal et al. review the latest developments on the characterization of Mason-Pfizer monkey virus (M-PMV) Gag interactions with the PM (Prchal et al., 2014). M-PMV, which belongs to Betaretroviruses, first assembles into virus-like particles (VLPs) in the pericentriolar region of the infected cell and therefore. Structural details of M-PMV MA binding to single phospholipids are discussed. Dick et al. describe the principles that govern Gag interactions with membranes, focusing on RSV and HIV-1 Gag (Dick and Vogt, 2014). The review defines lipid and membrane behavior, and discusses the complexities in determining how lipid and membrane behavior impact Gag membrane binding. Yandrapalli et al. review the role of plasma membrane lipids in HIV-1 Gag targeting and assembly, mainly focusing on membrane biophysics (Yandrapalli et al., 2014). Studies identified the 1,4,5-inositol trisphosphate receptor (IP3R), a channel mediating release of Ca2+ from ER stores, as a cellular factor differentially associated with HIV-1 Gag that might facilitate ESCRT function in virus budding. In a research article, Ehrlich et al. show that Gag modulates ER store gating and refilling (Ehrlich et al., 2014). It is shown that Gag accumulation at the plasma membrane required continuous IP3R activation. Elevation of Ca2+ level in the immediate vicinity of the plasma membrane is suggested to drive events that lead to stable membrane localization of assembling Gag. In their review, Alfadhli et al. focus on the functions of retroviral MA proteins, with an emphasis on the nucleic acid-binding capability of the HIV-1 MA protein and its effects on membrane binding (Alfadhli and Barklis, 2014). A review by Maldonado et al. discusses not only retroviral Gag-membrane interactions but also how Gag-Gag interactions contribute to the overall assembly process (Maldonado et al., 2014). Differences among retroviruses in Gag–Gag and Gag–membrane interactions implying various molecular aspects of the viral assembly pathway are described. Mariani et al. discuss the role of Gag and lipids during HIV-1 assembly in CD4+ T cells and macrophages (Mariani et al., 2014). Whereas, HIV-1 assembly and budding in macrophages is thought to follow the same general Gag-driven mechanism as in T-lymphocytes, the HIV-1 cycle in macrophage exhibits specific features. How Gag interacts with membrane lipids and what are the mechanisms involved in the interaction between the different membrane nanodomains within the assembly platform are not fully understood. Vlach et al. discuss the structural and molecular determinants of HIV-1 Gag binding to the plasma membrane (Vlach and Saad, 2015). This review emphasizes the structural findings on HIV-1 and HIV-2 MA binding to PM lipids and how these studies may advance our understanding of the overall Gag-membrane binding mechanism. The ninth article of this issue discusses the assembly and budding mechanisms of filoviruses including Marbug (MARV) and EBOV viruses (Stahelin, 2014). EBOV budding occurs from the inner leaflet of the plasma membrane (PM) and is driven by the matrix protein VP40, which binds to anionic lipid membranes. The review by Stahelin describes what is known regarding VP40 membrane interactions and what answers will fill the gaps. Collectively, the articles published under this special topic remarkably enriched our understanding of the role of membrane lipids during assembly, egress and release.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Chu, H., Wang, J. J., and Spearman, P. (2010). Human immunodeficiency virus type-1 Gag and host vesicular trafficking pathways. Curr. Top. Microbiol. Immunol. 339, 67–84. doi: 10.1007/978-3-642-02175-6_4
Chukkapalli, V., Hogue, I. B., Boyko, V., Hu, W.-S., and Ono, A. (2008). Interaction between HIV-1 Gag matrix domain and phosphatidylinositol-(4,5)-bisphosphate is essential for efficient Gag-membrane binding. J. Virol. 82, 2405–2417. doi: 10.1128/JVI.01614-07
Chukkapalli, V., Inlora, J., Todd, G. C., and Ono, A. (2013). Evidence in support of RNA-mediated inhibition of phosphatidylserine-dependent HIV-1 Gag membrane binding in cells. J. Virol. 87, 7155–7159. doi: 10.1128/JVI.00075-13
Chukkapalli, V., Oh, S. J., and Ono, A. (2010). Opposing mechanisms involving RNA and lipids regulate HIV-1 Gag membrane binding through the highly basic region of the matrix domain. Proc. Natl. Acad. Sci. U.S.A. 107, 1600–1605. doi: 10.1073/pnas.0908661107
Datta, S. A., Heinrich, F., Raghunandan, S., Krueger, S., Curtis, J. E., Rein, A., et al. (2011). HIV-1 Gag extension: conformational changes require simultaneous interaction with membrane and nucleic acid. J. Mol. Biol. 406, 205–215. doi: 10.1016/j.jmb.2010.11.051
Datta, S. A. K., Curtis, J. E., Ratcliff, W., Clark, P. K., Crist, R. M., Rein, A., et al. (2007). Conformation of the HIV-1 Gag protein in solution. J. Mol. Biol. 365, 812–824. doi: 10.1016/j.jmb.2006.10.073
Ehrlich, L. S., Medina, G. N., Photiadis, S., Whittredge, P. B., Watanabe, S., Taraska, J. W., et al. (2014). Tsg101 regulates PI(4,5)P2/Ca(2+) signaling for HIV-1 Gag assembly. Front. Microbiol. 5:234. doi: 10.3389/fmicb.2014.00234
Finzi, A., Orthwein, A., Mercier, J., and Cohen, E. A. (2007). Productive human immunodeficiency virus type 1 assembly takes place at the plasma membrane. J. Virol. 81, 7476–7490. doi: 10.1128/JVI.00308-07
Grigorov, B., Arcanger, F., Roingeard, P., Darlix, J. L., and Muriaux, D. (2006). Assembly of infectious HIV-1 in human epithelial and T-lymphoblastic cell lines. J. Mol. Biol. 359, 848–862. doi: 10.1016/j.jmb.2006.04.017
Hamard-Peron, E., Juilliard, F., Saad, J. S., Roy, C., Roingeard, P., Summers, M. F., et al. (2010). Targeting of MuLV Gag to the plasma membrane is mediated by PI(4,5)P2/PS and a polybasic region in the Matrix. J. Virol. 84, 503–515. doi: 10.1128/JVI.01134-09
Inlora, J., Collins, D. R., Trubin, M. E., Chung, J. Y., and Ono, A. (2014). Membrane binding and subcellular localization of retroviral Gag proteins are differentially regulated by MA interactions with phosphatidylinositol-(4,5)-bisphosphate and RNA. MBio 5, e02202. doi: 10.1128/mBio.02202-14
Jouvenet, N., Neil, S. J. D., Bess, C., Johnson, M. C., Virgen, C. A., Simon, S. M., et al. (2006). Plasma membrane is the site of productive HIV-1 particle assembly. PLoS Biol. 4:e435. doi: 10.1371/journal.pbio.0040435
Kutluay, S. B., Zang, T., Blanco-Melo, D., Powell, C., Jannain, D., Errando, M., et al. (2014). Global Changes in the RNA Binding Specificity of HIV-1 Gag Regulate Virion Genesis. Cell 159, 1096–1109. doi: 10.1016/j.cell.2014.09.057
Maldonado, J. O., Martin, J. L., Mueller, J. D., Zhang, W., and Mansky, L. M. (2014). New insights into retroviral Gag-Gag and Gag-membrane interactions. Front. Microbiol. 5:302. doi: 10.3389/fmicb.2014.00302
Mariani, C., Desdouits, M., Favard, C., Benaroch, P., and Muriaux, D. M. (2014). Role of Gag and lipids during HIV-1 assembly in CD4(+) T cells and macrophages. Front. Microbiol. 5:312. doi: 10.3389/fmicb.2014.00312
Ono, A., Ablan, S. D., Lockett, S. J., Nagashima, K., and Freed, E. O. (2004). Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane. Proc. Natl. Acad. Sci. U.S.A. 101, 14889–14894. doi: 10.1073/pnas.0405596101
Welsch, S., Keppler, O. T., Habermann, A., Allespach, I., Krijnse-Locker, J., and Kräusslich, H.-G. (2007). HIV-1 buds predominantly at the plasma membrane of primary human macrophages. PLoS Pathog. 3:e36. doi: 10.1371/journal.ppat.0030036
Keywords: retroviruses, HIV-1, Gag, Matrix, membrane, NMR, Ebola, PI(4, 5)P2
Citation: Saad JS and Muriaux DM (2015) Editorial: Role of lipids in virus assembly. Front. Microbiol. 6:410. doi: 10.3389/fmicb.2015.00410
Received: 17 April 2015; Accepted: 20 April 2015;
Published: 05 May 2015.
Edited and reviewed by: Akio Adachi, Tokushima University Graduate School, Japan
Copyright © 2015 Saad and Muriaux. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jamil S. Saad, firstname.lastname@example.org