Unraveling a Three-Step Spatiotemporal Mechanism of Triggering of Receptor-Induced Nipah Virus Fusion and Cell Entry


Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.


Vyšlo v časopise: Unraveling a Three-Step Spatiotemporal Mechanism of Triggering of Receptor-Induced Nipah Virus Fusion and Cell Entry. PLoS Pathog 9(11): e32767. doi:10.1371/journal.ppat.1003770
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003770

Souhrn

Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.


Zdroje

1. LubySP, HossainMJ, GurleyES, AhmedBN, BanuS, et al. (2009) Recurrent zoonotic transmission of Nipah virus into humans, Bangladesh, 2001–2007. Emerg Infect Dis 15: 1229–1235.

2. ChuaKB, BelliniWJ, RotaPA, HarcourtBH, TaminA, et al. (2000) Nipah virus: a recently emergent deadly paramyxovirus. Science 288: 1432–1435.

3. AguilarHC, IorioRM (2012) Henipavirus Membrane Fusion and Viral Entry. Current topics in microbiology and immunology 359: 79–94.

4. KrzyzaniakMA, ZumsteinMT, GerezJA, PicottiP, HeleniusA (2013) Host Cell Entry of Respiratory Syncytial Virus Involves Macropinocytosis Followed by Proteolytic Activation of the F Protein. Plos Pathogens 9: e1003309.

5. PernetO, PohlC, AinouzeM, KwederH, BucklandR (2009) Nipah virus entry can occur by macropinocytosis. Virology 395: 298–311.

6. SmithAE, HeleniusA (2004) How viruses enter animal cells. Science 304: 237–242.

7. WhiteJM, DelosSE, BrecherM, SchornbergK (2008) Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol 43: 189–219.

8. WongKT, ShiehWJ, KumarS, NorainK, AbdullahW, et al. (2002) Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 161: 2153–2167.

9. DutchRE (2010) Entry and fusion of emerging paramyxoviruses. PLoS Pathog 6: e1000881.

10. LambRA, PatersonRG, JardetzkyTS (2006) Paramyxovirus membrane fusion: lessons from the F and HN atomic structures. Virology 344: 30–37.

11. PlemperRK, BrindleyMA, IorioRM (2011) Structural and mechanistic studies of measles virus illuminate paramyxovirus entry. PLoS pathogens 7: e1002058.

12. XuY, LouZ, LiuY, ColeDK, SuN, et al. (2004) Crystallization and preliminary crystallographic analysis of the fusion core from two new zoonotic paramyxoviruses, Nipah virus and Hendra virus. Acta Crystallogr D Biol Crystallogr 60: 1161–1164.

13. ChangA, DutchRE (2012) Paramyxovirus fusion and entry: multiple paths to a common end. Viruses 4: 613–636.

14. BonaparteMI, DimitrovAS, BossartKN, CrameriG, MungallBA, et al. (2005) From The Cover: Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus. Proc Natl Acad Sci U S A 102: 10652–10657.

15. NegreteOA, LevroneyEL, AguilarHC, Bertolotti-CiarletA, NazarianR, et al. (2005) EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 436: 401–405.

16. NegreteOA, WolfMC, AguilarHC, EnterleinS, WangW, et al. (2006) Two key residues in ephrinB3 are critical for its use as an alternative receptor for Nipah virus. PLoS Pathog 2: e7.

17. IorioRM, MelansonVR, MahonPJ (2009) Glycoprotein interactions in paramyxovirus fusion. Future Virol 4: 335–351.

18. SmithEC, PopaA, ChangA, MasanteC, DutchRE (2009) Viral entry mechanisms: the increasing diversity of paramyxovirus entry. FEBS J 276: 7217–7227.

19. BoseS, WelchBD, KorsCA, YuanP, JardetzkyTS, et al. (2011) Structure and mutagenesis of the parainfluenza virus 5 hemagglutinin-neuraminidase stalk domain reveals a four-helix bundle and the role of the stalk in fusion promotion. Journal of virology 85: 12855–12866.

20. YuanP, SwansonKA, LeserGP, PatersonRG, LambRA, et al. (2011) Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk. Proceedings of the National Academy of Sciences of the United States of America 108: 14920–14925.

21. MaarD, HarmonB, ChuD, SchulzB, AguilarHC, et al. (2012) Cysteines in the stalk of the nipah virus G glycoprotein are located in a distinct subdomain critical for fusion activation. Journal of virology 86: 6632–6642.

22. BoseS, ZokarkarA, WelchBD, LeserGP, JardetzkyTS, et al. (2012) Fusion activation by a headless parainfluenza virus 5 hemagglutinin-neuraminidase stalk suggests a modular mechanism for triggering. Proceedings of the National Academy of Sciences of the United States of America 109: E2625–2634.

23. ItoM, NishioM, KawanoM, KusagawaS, KomadaH, et al. (1997) Role of a single amino acid at the amino terminus of the simian virus 5 F2 subunit in syncytium formation. Journal of virology 71: 9855–9858.

24. BowdenTA, AricescuAR, GilbertRJ, GrimesJM, JonesEY, et al. (2008) Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2. Nat Struct Mol Biol 15: 567–572.

25. XuK, RajashankarKR, ChanYP, HimanenJP, BroderCC, et al. (2008) Host cell recognition by the henipaviruses: crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3. Proc Natl Acad Sci U S A 105: 9953–9958.

26. BieringSB, HuangA, VuAT, RobinsonLR, Bradel-TrethewayB, et al. (2012) N-Glycans on the Nipah Virus Attachment Glycoprotein Modulate Fusion and Viral Entry as They Protect against Antibody Neutralization. Journal of virology 86: 11991–12002.

27. BishopKA, StantchevTS, HickeyAC, KhetawatD, BossartKN, et al. (2007) Identification of Hendra virus G glycoprotein residues that are critical for receptor binding. J Virol 81: 5893–5901.

28. NegreteOA, ChuD, AguilarHC, LeeB (2007) Single Amino Acid Changes in the Nipah and Hendra Virus Attachment Glycoproteins Distinguish EphrinB2 from EphrinB3 Usage. J Virol 81: 10804–10814.

29. AguilarHC, MatreyekKA, FiloneCM, HashimiST, LevroneyEL, et al. (2006) N-glycans on Nipah virus fusion protein protect against neutralization but reduce membrane fusion and viral entry. J Virol 80: 4878–4889.

30. BossartKN, WangLF, FloraMN, ChuaKB, LamSK, et al. (2002) Membrane fusion tropism and heterotypic functional activities of the Nipah virus and Hendra virus envelope glycoproteins. J Virol 76: 11186–11198.

31. AguilarHC, AspericuetaV, RobinsonLR, AanensenKE, LeeB (2010) A quantitative and kinetic fusion protein-triggering assay can discern distinct steps in the nipah virus membrane fusion cascade. J Virol 84: 8033–8041.

32. AguilarHC, MatreyekKA, ChoiDY, FiloneCM, YoungS, et al. (2007) Polybasic KKR motif in the cytoplasmic tail of Nipah virus fusion protein modulates membrane fusion by inside-out signaling. J Virol 81: 4520–4532.

33. LuX, LiuQ, Benavides-MontanoJA, NicolaAV, AstonDE, et al. (2013) Detection of Receptor-Induced Glycoprotein Conformational Changes on Enveloped Virions Using Confocal Micro-Raman Spectroscopy. Journal of virology 87 (6) 3130–42.

34. AguilarHC, AtamanZA, AspericuetaV, FangAQ, StroudM, et al. (2009) A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F). J Biol Chem 284: 1628–1635.

35. ZhuQ, BieringSB, MirzaAM, GrasseschiBA, MahonPJ, et al. (2013) Individual N-glycans added at intervals along the stalk of the Nipah virus G protein prevent fusion but do not block the interaction with the homologous F protein. Journal of virology 87: 3119–3129.

36. IorioRM, MahonPJ (2008) Paramyxoviruses: different receptors - different mechanisms of fusion. Trends Microbiol 16: 135–137.

37. BrindleyMA, SuterR, SchestakI, KissG, WrightER, PlemperRK (2013) A Stabilized Headless Measles Virus Attachment Protein Stalk Efficiently Triggers Membrane Fusion. Journal of Virology 87 (21) 11693–703.

38. BrindleyMA, TakedaM, PlattetP, PlemperRK (2012) Triggering the measles virus membrane fusion machinery. Proceedings of the National Academy of Sciences of the United States of America 109: E3018–3027.

39. NavaratnarajahCK, OezguenN, RuppL, KayL, LeonardVH, et al. (2011) The heads of the measles virus attachment protein move to transmit the fusion-triggering signal. Nature structural & molecular biology 18: 128–134.

40. LevroneyEL, AguilarHC, FulcherJA, KohatsuL, PaceKE, et al. (2005) Novel innate immune functions for galectin-1: galectin-1 inhibits cell fusion by Nipah virus envelope glycoproteins and augments dendritic cell secretion of proinflammatory cytokines. J Immunol 175: 413–420.

41. PatchJR, CrameriG, WangLF, EatonBT, BroderCC (2007) Quantitative analysis of Nipah virus proteins released as virus-like particles reveals central role for the matrix protein. Virol J 4: 1.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2013 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa