#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Cyclophilin A Associates with Enterovirus-71 Virus Capsid and Plays an Essential Role in Viral Infection as an Uncoating Regulator


Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) in Asia-Pacific region and caused over one million infection cases and nine hundred deaths in the year of 2010 in China mainland. EV71 is known to infect the young children for the sake of their undeveloped immune system. Unlike other Enterovirus (e.g. coxsackievirus), EV71 could cause severe aseptic meningitis, encephalitis, myocarditis, and acute flaccid paralysis, thus leading to high fatality rates. There is no clinically applied therapeutics. In this work, we used CypA inhibitors as bioprobes to show that CypA played an essential role in EV71 proliferation. We also elucidated the mechanism by which CypA interacted with the EV71 VP1 H-I loop and functioned as an uncoating regulator in EV71 entry step. Since there are several non-immunosuppressive CypA inhibitors, e.g. NIM-811 and Debio-025, have been reported to show antiviral potency, our results provide a potential way to discover clinical therapeutics against EV71 infection.


Vyšlo v časopise: Cyclophilin A Associates with Enterovirus-71 Virus Capsid and Plays an Essential Role in Viral Infection as an Uncoating Regulator. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004422
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004422

Souhrn

Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) in Asia-Pacific region and caused over one million infection cases and nine hundred deaths in the year of 2010 in China mainland. EV71 is known to infect the young children for the sake of their undeveloped immune system. Unlike other Enterovirus (e.g. coxsackievirus), EV71 could cause severe aseptic meningitis, encephalitis, myocarditis, and acute flaccid paralysis, thus leading to high fatality rates. There is no clinically applied therapeutics. In this work, we used CypA inhibitors as bioprobes to show that CypA played an essential role in EV71 proliferation. We also elucidated the mechanism by which CypA interacted with the EV71 VP1 H-I loop and functioned as an uncoating regulator in EV71 entry step. Since there are several non-immunosuppressive CypA inhibitors, e.g. NIM-811 and Debio-025, have been reported to show antiviral potency, our results provide a potential way to discover clinical therapeutics against EV71 infection.


Zdroje

1. LiuJ, FarmerJDJr, LaneWS, FriedmanJ, WeissmanI, et al. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66: 807–815.

2. ZhouD, MeiQ, LiJ, HeH (2012) Cyclophilin A and viral infections. Biochem Biophys Res Commun 424: 647–650.

3. Bienkowska-HabaM, PatelHD, SappM (2009) Target cell cyclophilins facilitate human papillomavirus type 16 infection. PLoS Pathog 5: e1000524.

4. ThaliM, BukovskyA, KondoE, RosenwirthB, WalshCT, et al. (1994) Functional association of cyclophilin A with HIV-1 virions. Nature 372: 363–365.

5. FrankeEK, YuanHE, LubanJ (1994) Specific incorporation of cyclophilin A into HIV-1 virions. Nature 372: 359–362.

6. BrunsK, FossenT, WrayV, HenkleinP, TessmerU, et al. (2003) Structural characterization of the HIV-1 Vpr N terminus: evidence of cis/trans-proline isomerism. J Biol Chem 278: 43188–43201.

7. ColganJ, YuanHE, FrankeEK, LubanJ (1996) Binding of the human immunodeficiency virus type 1 Gag polyprotein to cyclophilin A is mediated by the central region of capsid and requires Gag dimerization. J Virol 70: 4299–4310.

8. PushkarskyT, ZybarthG, DubrovskyL, YurchenkoV, TangH, et al. (2001) CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A. Proceedings of the National Academy of Sciences of the United States of America 98: 6360–6365.

9. ShahVB, ShiJ, HoutDR, OztopI, KrishnanL, et al. (2013) The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J Virol 87: 422–432.

10. WatashiK, IshiiN, HijikataM, InoueD, MurataT, et al. (2005) Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 19: 111–122.

11. YangF, RobothamJM, NelsonHB, IrsiglerA, KenworthyR, et al. (2008) Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 82: 5269–5278.

12. KaulA, StaufferS, BergerC, PertelT, SchmittJ, et al. (2009) Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog 5: e1000546.

13. LiuZ, YangF, RobothamJM, TangH (2009) Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol 83: 6554–6565.

14. CiesekS, SteinmannE, WedemeyerH, MannsMP, NeytsJ, et al. (2009) Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A. Hepatology 50: 1638–1645.

15. HanoulleX, BadilloA, WieruszeskiJM, VerdegemD, LandrieuI, et al. (2009) Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. J Biol Chem 284: 13589–13601.

16. TellinghuisenTL, FossKL, TreadawayJC, RiceCM (2008) Identification of residues required for RNA replication in domains II and III of the hepatitis C virus NS5A protein. J Virol 82: 1073–1083.

17. Bienkowska-HabaM, WilliamsC, KimSM, GarceaRL, SappM (2012) Cyclophilins facilitate dissociation of the human papillomavirus type 16 capsid protein L1 from the L2/DNA complex following virus entry. J Virol 86: 9875–9887.

18. SunY, WangY, ShanC, ChenC, XuP, et al. (2012) Enterovirus 71 VPg uridylation uses a two-molecular mechanism of 3D polymerase. J Virol 86: 13662–13671.

19. LouZ, SunY, RaoZ (2013) Current progress in antiviral strategies. Trends in Pharmacological Sciences 35: 86–102 10.1016/j.tips.2013.1011.1006.

20. ChenC, WangY, ShanC, SunY, XuP, et al. (2013) Crystal Structure of Enterovirus 71 RNA-Dependent RNA Polymerase Complexed with Its Protein Primer VPg: Implication for a trans Mechanism of VPg Uridylylation. J Virol 87: 5755–5768.

21. ChenP, SongZ, QiY, FengX, XuN, et al. (2012) Molecular determinants of enterovirus 71 viral entry: cleft around GLN-172 on VP1 protein interacts with variable region on scavenge receptor B 2. J Biol Chem 287: 6406–6420.

22. TuthillTJ, GroppelliE, HogleJM, RowlandsDJ (2010) Picornaviruses. Current topics in microbiology and immunology 343: 43–89.

23. NishimuraY, ShimojimaM, TanoY, MiyamuraT, WakitaT, et al. (2009) Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 15: 794–797.

24. YamayoshiS, YamashitaY, LiJ, HanagataN, MinowaT, et al. (2009) Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 15: 798–801.

25. Neculai D, Schwake M, Ravichandran M, Zunke F, Collins RF, et al.. (2013) Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature.

26. TanCW, PohCL, SamIC, ChanYF (2013) Enterovirus 71 uses cell surface heparan sulfate glycosaminoglycan as an attachment receptor. J Virol 87: 611–620.

27. YangSL, ChouYT, WuCN, HoMS (2011) Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity. J Virol 85: 11809–11820.

28. NiS, YuanY, HuangJ, MaoX, LvM, et al. (2009) Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach. J Med Chem 52: 5295–5298.

29. ZhouH, SunY, GuoY, LouZ (2013) Structural perspective on the formation of ribonucleoprotein complex in negative-sense single-stranded RNA viruses. Trends Microbiol 21: 475–484.

30. LiuX, SunL, YuM, WangZ, XuC, et al. (2009) Cyclophilin A interacts with influenza A virus M1 protein and impairs the early stage of the viral replication. Cell Microbiol 11: 730–741.

31. LiuX, ZhaoZ, XuC, SunL, ChenJ, et al. (2012) Cyclophilin A restricts influenza A virus replication through degradation of the M1 protein. PLoS One 7: e31063.

32. PlevkaP, PereraR, CardosaJ, KuhnRJ, RossmannMG (2012) Crystal structure of human enterovirus 71. Science 336: 1274.

33. ZydowskyLD, EtzkornFA, ChangHY, FergusonSB, StolzLA, et al. (1992) Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition. Protein Sci 1: 1092–1099.

34. ChatterjiU, BobardtM, SelvarajahS, YangF, TangH, et al. (2009) The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J Biol Chem 284: 16998–17005.

35. WangX, PengW, RenJ, HuZ, XuJ, et al. (2012) A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol 19: 424–429.

36. De ColibusL, WangX, SpyrouJA, KellyJ, RenJ, et al. (2014) More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. Nat Struct Mol Biol 21: 282–288.

37. NishimuraY, LeeK, HafensteinS, KataokaC, WakitaT, et al. (2013) Enterovirus 71 Binding to PSGL-1 on Leukocytes: VP1-145 Acts as a Molecular Switch to Control Receptor Interaction. PLoS Pathogen 9: e1003511.

38. LeeH, CifuenteJO, AshleyRE, ConwayJF, MakhovAM, et al. (2013) A strain-specific epitope of Enterovirus 71 identified by cryoEM of the complex with Fab from 2 neutralizing antibody. J Virol 87: 11363–11370.

39. HuotariJ, HeleniusA (2011) Endosome maturation. Embo J 30: 3481–3500.

40. MercerJ, SchelhaasM, HeleniusA (2010) Virus entry by endocytosis. Annu Rev Biochem 79: 803–833.

41. DamskerJM, BukrinskyMI, ConstantSL (2007) Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A. J Leukoc Biol 82: 613–618.

42. GoldstoneDC, YapMW, RobertsonLE, HaireLF, TaylorWR, et al. (2010) Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular interface. Cell Host Microbe 8: 248–259.

43. PanJ, NarayananB, ShahS, YoderJD, CifuenteJO, et al. (2011) Single amino acid changes in the virus capsid permit coxsackievirus B3 to bind decay-accelerating factor. J Virol 85: 7436–7443.

44. RasaiyaahJ, TanCP, FletcherAJ, PriceAJ, BlondeauC, et al. (2013) HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503: 402–405.

45. LiY, KarAK, SodroskiJ (2009) Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A. J Virol 83: 10951–10962.

46. LinYC, WuCN, ShihSR, HoMS (2002) Characterization of a Vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine 20: 2485–2493.

47. ZhongJ, GastaminzaP, ChengG, KapadiaS, KatoT, et al. (2005) Robust hepatitis C virus infection in vitro. Proceedings of the National Academy of Sciences of the United States of America 102: 9294–9299.

48. CordeyS, PettyTJ, SchiblerM, MartinezY, GerlachD, et al. (2012) Identification of site-specific adaptations conferring increased neural cell tropism during human enterovirus 71 infection. PLoS Pathog 8: e1002826.

49. FischerG, Wittmann-LieboldB, LangK, KiefhaberT, SchmidFX (1989) Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337: 476–478.

50. GalatA, MetcalfeSM (1995) Peptidylproline cis/trans isomerases. Progress in biophysics and molecular biology 63: 67–118.

51. HubnerD, DrakenbergT, ForsenS, FischerG (1991) Peptidyl-prolyl cis-trans isomerase activity as studied by dynamic proton NMR spectroscopy. FEBS Lett 284: 79–81.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

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

#ADS_BOTTOM_SCRIPTS#