Ebola virus (EBOV) is an enveloped filamentous virus that causes severe hemorrhagic fever in humans and nonhuman primates with up to 90% fatality. Accumulating evidence indicates that various viruses, including EBOV, exploit the host apoptotic clearance machinery to enhance their entry into host cells by externalizing phosphatidylserine (PS) in the viral envelope. PS is typically distributed in the inner layer of the plasma membrane (PM) in normal cells. Progeny EBOV virions bud from the PM of infected cells, suggesting that PS is likely flipped to the outer leaflet of the envelope of Ebola virions. Currently, the intracellular dynamics of PS during EBOV infection are poorly understood. This review summarizes recent progress in determining the molecular mechanism of externalization of PS in the envelope of EBOV particles. We also discuss future directions and how viral apoptotic mimicry could be targeted for therapeutics.
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References
1.
Adu-GyamfiE., JohnsonK.A., FraserM.E., ScottJ.L., SoniS.P., JonesK.R., et al. (2015). Host cell plasma membrane phosphatidylserine regulates the assembly and budding of Ebola virus. J Virol, 89, 9440–9453.
2.
Alder-BaerensN., LismanQ., LuongL., PomorskiT., and HolthuisJ.C. (2006). Loss of P4 ATPases Drs2p and Dnf3p disrupts aminophospholipid transport and asymmetry in yeast post-Golgi secretory vesicles. Mol Biol Cell, 17, 1632–1642.
3.
BhattacharyyaS., ZagorskaA., LewE.D., ShresthaB., RothlinC.V., NaughtonJ., et al. (2013). Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe, 14, 136–147.
CDC. (2016). 2014 Ebola outbreak in West Africa–case counts 2016. Available at www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html (last accessed March21, 2018).
7.
ChenY.H., DuW., HagemeijerM.C., TakvorianP.M., PauC., CaliA., et al. (2015). Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell, 160, 619–630.
8.
CheshenkoN., PierceC., and HeroldB.C. (2018). Herpes simplex viruses activate phospholipid scramblase to redistribute phosphatidylserines and Akt to the outer leaflet of the plasma membrane and promote viral entry. PLoS Pathog, 14, e1006766.
9.
CoteM., MisasiJ., RenT., BruchezA., LeeK., FiloneC.M., et al. (2011). Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature, 477, 344–348.
10.
DespresP., FlamandM., CeccaldiP.E., and DeubelV. (1996). Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol, 70, 4090–4096.
HankinsH.M., BaldridgeR.D., XuP., and GrahamT.R. (2015). Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution. Traffic, 16, 35–47.
13.
HuntC.L., KolokoltsovA.A., DaveyR.A., and MauryW. (2011). The Tyro3 receptor kinase Axl enhances macropinocytosis of Zaire ebolavirus. J Virol, 85, 334–347.
14.
JemielityS., WangJ.J., ChanY.K., AhmedA.A., LiW., MonahanS., et al. (2013). TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS Pathog, 9, e1003232.
15.
JohnsonK.A., TaghonG.J., ScottJ.L., and StahelinR.V. (2016). The Ebola Virus matrix protein, VP40, requires phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for extensive oligomerization at the plasma membrane and viral egress. Sci Rep, 6, 19125.
16.
KallstromG., WarfieldK.L., SwensonD.L., MortS., PanchalR.G., RuthelG., et al. (2005). Analysis of Ebola virus and VLP release using an immunocapture assay. J Virol Methods, 127, 1–9.
17.
KondratowiczA.S., LennemannN.J., SinnP.L., DaveyR.A., HuntC.L., Moller-TankS., et al. (2011). T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci U S A, 108, 8426–8431.
18.
Krejbich-TrototP., DenizotM., HoarauJ.J., Jaffar-BandjeeM.C., DasT., and GasqueP. (2011). Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses. FASEB J, 25, 314–325.
19.
KurodaM., FujikuraD., NanboA., MarziA., NoyoriO., KajiharaM., et al. (2015). Interaction between TIM-1 and NPC1 is important for cellular entry of Ebola virus. J Virol, 89, 6481–6493.
20.
LaliberteJ.P., and MossB. (2009). Appraising the apoptotic mimicry model and the role of phospholipids for poxvirus entry. Proc Natl Acad Sci U S A, 106, 17517–17521.
21.
LevineB., HuangQ., IsaacsJ.T., ReedJ.C., GriffinD.E., and HardwickJ.M. (1993). Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature, 361, 739–742.
22.
LiuY., LiuH., ZouJ., ZhangB., and YuanZ. (2014). Dengue virus subgenomic RNA induces apoptosis through the Bcl-2-mediated PI3k/Akt signaling pathway. Virology, 448, 15–25.
23.
Maruri-AvidalL., WeisbergA.S., and MossB. (2013). Direct formation of vaccinia virus membranes from the endoplasmic reticulum in the absence of the newly characterized L2-interacting protein A30.5. J Virol, 87, 12313–12326.
24.
MeertensL., CarnecX., LecoinM.P., RamdasiR., Guivel-BenhassineF., LewE., et al. (2012). The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe, 12, 544–557.
25.
MercerJ., and HeleniusA. (2008). Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science, 320, 531–535.
26.
Moller-TankS., KondratowiczA.S., DaveyR.A., RennertP.D., and MauryW. (2013). Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry. J Virol, 87, 8327–8341.
27.
MorizonoK., and ChenI.S. (2014). Role of phosphatidylserine receptors in enveloped virus infection. J Virol, 88, 4275–4290.
28.
MorizonoK., XieY., OlafsenT., LeeB., DasguptaA., WuA.M., et al. (2011). The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. Cell Host Microbe, 9, 286–298.
29.
MukhopadhyayS., KuhnR.J., and RossmannM.G. (2005). A structural perspective of the flavivirus life cycle. Nat Rev Microbiol, 3, 13–22.
30.
NanboA., ImaiM., WatanabeS., NodaT., TakahashiK., NeumannG., et al. (2010). Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog, 6, e1001121.
31.
NanboA., MaruyamaJ., ImaiM., UjieM., FujiokaY., NishideS., et al. (2018). Ebola virus requires a host scramblase for externalization of phosphatidylserine on the surface of viral particles. PLoS Pathog, 14, e1006848.
32.
NatarajanP., WangJ., HuaZ., and GrahamT.R. (2004). Drs2p-coupled aminophospholipid translocase activity in yeast Golgi membranes and relationship to in vivo function. Proc Natl Acad Sci U S A, 101, 10614–10619.
33.
NodaT., SagaraH., SuzukiE., TakadaA., KidaH., and KawaokaY. (2002). Ebola virus VP40 drives the formation of virus-like filamentous particles along with GP. J Virol, 76, 4855–4865.
34.
OlejnikJ., AlonsoJ., SchmidtK.M., YanZ., WangW., MarziA., et al. (2013). Ebola virus does not block apoptotic signaling pathways. J Virol, 87, 5384–5396.
35.
SaeedM.F., KolokoltsovA.A., AlbrechtT., and DaveyR.A. (2010). Cellular entry of Ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog, 6, e1001110.
36.
SanchezA., GeisbertT., and FeldmannH. (2007). Filoviridae: Marburg and Ebola viruses. In Fields Virology, 5th ed. KnipeD.M., and HowleyP.M., eds. (Lippincott/Williams & Wilkins Co, Philadelphia, PA), pp. 1409–1448.
37.
SantiagoC., BallesterosA., TamiC., Martinez-MunozL., KaplanG.G., and CasasnovasJ.M. (2007). Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity, 26, 299–310.
38.
SegawaK., and NagataS. (2015). An apoptotic ‘Eat Me’ signal: phosphatidylserine exposure. Trends Cell Biol, 25, 639–650.
39.
ShimojimaM., IkedaY., and KawaokaY. (2007). The mechanism of Axl-mediated Ebola virus infection. J Infect Dis, 196Suppl 2, S259–S263.
40.
ShimojimaM., StroherU., EbiharaH., FeldmannH., and KawaokaY. (2012). Identification of cell surface molecules involved in dystroglycan-independent Lassa virus cell entry. J Virol, 86, 2067–2078.
41.
ShimojimaM., TakadaA., EbiharaH., NeumannG., FujiokaK., IrimuraT., et al. (2006). Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol, 80, 10109–10116.
42.
SoaresM.M., KingS.W., and ThorpeP.E. (2008). Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases. Nat Med, 14, 1357–1362.
43.
SoniS.P., and StahelinR.V. (2014). The Ebola virus matrix protein VP40 selectively induces vesiculation from phosphatidylserine-enriched membranes. J Biol Chem, 289, 33590–33597.
44.
StahelinR.V. (2014). Membrane binding and bending in Ebola VP40 assembly and egress. Front Microbiol, 5, 300.
45.
StanfieldG.M., and HorvitzH.R. (2000). The ced-8 gene controls the timing of programmed cell deaths in C. elegans. Mol Cell, 5, 423–433.
46.
StittT.N., ConnG., GoreM., LaiC., BrunoJ., RadziejewskiC., et al. (1995). The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell, 80, 661–670.
47.
SuH.L., LiaoC.L., and LinY.L. (2002). Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. J Virol, 76, 4162–4171.
48.
SuzukiJ., DenningD.P., ImanishiE., HorvitzH.R., and NagataS. (2013). Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science, 341, 403–406.
49.
SuzukiJ., ImanishiE., and NagataS. (2016). Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc Natl Acad Sci U S A, 113, 9509–9514.
50.
SuzukiJ., UmedaM., SimsP.J., and NagataS. (2010). Calcium-dependent phospholipid scrambling by TMEM16F. Nature, 468, 834–838.
51.
WangH., ShiY., SongJ., QiJ., LuG., YanJ., et al. (2016). Ebola viral glycoprotein bound to its endosomal receptor Niemann-Pick C1. Cell, 164, 258–268.
52.
WatanabeS., WatanabeT., NodaT., TakadaA., FeldmannH., JasenoskyL.D., et al. (2004). Production of novel Ebola virus-like particles from cDNAs: an alternative to Ebola virus generation by reverse genetics. J Virol, 78, 999–1005.
53.
WHO. (2018). Ebola situation reports: Democratic Republic of the Congo. Available at www.who.int/ebola/situation-reports/drc-2018/en (last accessed September16, 2018).
54.
WongG., and KobingerG.P. (2015). Backs against the wall: novel and existing strategies used during the 2014–2015 Ebola virus outbreak. Clin Microbiol Rev, 28, 593–601.
55.
YeungT., GilbertG.E., ShiJ., SilviusJ., KapusA., and GrinsteinS. (2008). Membrane phosphatidylserine regulates surface charge and protein localization. Science, 319, 210–213.
56.
ZachowskiA. (1993). Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J, 294 (Pt 1), 1–14.
57.
ZaitsevaE., ZaitsevE., MelikovK., ArakelyanA., MarinM., VillasmilR., et al. (2017). Fusion stage of HIV-1 entry depends on virus-induced cell surface exposure of phosphatidylserine. Cell Host Microbe, 22, 99–110e7.
58.
ZwaalR.F., ComfuriusP., and BeversE.M. (2004). Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta, 1636, 119–128.
