The Human Polyoma JC Virus Agnoprotein Acts as a Viroporin

English version České info

Virus infections can result in a range of cellular injuries and commonly this involves both the plasma and intracellular membranes, resulting in enhanced permeability. Viroporins are a group of proteins that interact with plasma membranes modifying permeability and can promote the release of viral particles. While these proteins are not essential for virus replication, their activity certainly promotes virus growth. Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease resulting from lytic infection of oligodendrocytes by the polyomavirus JC virus (JCV). The genome of JCV encodes six major proteins including a small auxiliary protein known as agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to viral propagation at various stages in the replication cycle, including transcription, translation, processing of late viral proteins, assembly of virions, and viral propagation. Previous studies from our and other laboratories have indicated that JCV agnoprotein plays an important, although as yet incompletely understood role in the propagation of JCV. Here, we demonstrate that agnoprotein possesses properties commonly associated with viroporins. Our findings demonstrate that: (i) A deletion mutant of agnoprotein is defective in virion release and viral propagation; (ii) Agnoprotein localizes to the ER early in infection, but is also found at the plasma membrane late in infection; (iii) Agnoprotein is an integral membrane protein and forms homo-oligomers; (iv) Agnoprotein enhances permeability of cells to the translation inhibitor hygromycin B; (v) Agnoprotein induces the influx of extracellular Ca²⁺; (vi) The basic residues at amino acid positions 8 and 9 of agnoprotein key are determinants of the viroporin activity. The viroporin-like properties of agnoprotein result in increased membrane permeability and alterations in intracellular Ca²⁺ homeostasis leading to membrane dysfunction and enhancement of virus release.

Vyšlo v časopise: The Human Polyoma JC Virus Agnoprotein Acts as a Viroporin. PLoS Pathog 6(3): e32767. doi:10.1371/journal.ppat.1000801
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000801

Souhrn

Zdroje

1. WelschS

MullerB

KrausslichHG

2007 More than one door - Budding of enveloped viruses through cellular membranes. FEBS Lett 581 2089 2097

2. CarrascoL

1995 Modification of membrane permeability by animal viruses. Adv Virus Res 45 61 112

3. AldabeR

BarcoA

CarrascoL

1996 Membrane permeabilization by poliovirus proteins 2B and 2BC. J Biol Chem 271 23134 23137

4. van KuppeveldFJ

HoenderopJG

SmeetsRL

WillemsPH

DijkmanHB

1997 Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release. Embo J 16 3519 3532

5. NewtonK

MeyerJC

BellamyAR

TaylorJA

1997 Rotavirus nonstructural glycoprotein NSP4 alters plasma membrane permeability in mammalian cells. J Virol 71 9458 9465

6. GonzalezME

CarrascoL

2003 Viroporins. FEBS Lett 552 28 34

7. NievaJL

AgirreA

NirS

CarrascoL

2003 Mechanisms of membrane permeabilization by picornavirus 2B viroporin. FEBS Lett 552 68 73

8. AgirreA

BarcoA

CarrascoL

NievaJL

2002 Viroporin-mediated membrane permeabilization. Pore formation by nonstructural poliovirus 2B protein. J Biol Chem 277 40434 40441

9. GriceAL

KerrID

SansomMS

1997 Ion channels formed by HIV-1 Vpu: a modelling and simulation study. FEBS Lett 405 299 304

10. MeltonJV

EwartGD

WeirRC

BoardPG

LeeE

2002 Alphavirus 6K proteins form ion channels. J Biol Chem 277 46923 46931

11. PintoLH

HolsingerLJ

LambRA

1992 Influenza virus M2 protein has ion channel activity. Cell 69 517 528

12. AlwineJC

1982 Evidence for simian virus 40 late transcriptional control: mixed infections of wild-type simian virus 40 and a late leader deletion mutant exhibit trans effects on late viral RNA synthesis. J Virol 42 798 803

13. HayN

Skolnik-DavidH

AloniY

1982 Attenuation in the control of SV40 gene expression. Cell 29 183 193

14. HayN

AloniY

1985 Attenuation of late simian virus 40 mRNA synthesis is enhanced by the agnoprotein and is temporally regulated in isolated nuclear systems. Mol Cell Biol 5 1327 1334

15. PiatakM

SubramanianKN

RoyP

WeissmanSM

1981 Late messenger RNA production by viable simian virus 40 mutants with deletions in the leader region. J Mol Biol 153 589 618

16. MargolskeeRF

NathansD

1983 Suppression of a VP1 mutant of simian virus 40 by missense mutations in serine codons of the viral agnogene. J Virol 48 405 409

17. MertzJE

MurphyA

BarkanA

1983 Mutants deleted in the agnogene of simian virus 40 define a new complementation group. J Virol 45 36 46

18. CarswellS

AlwineJC

1986 Simian virus 40 agnoprotein facilitates perinuclear-nuclear localization of VP1, the major capsid protein. J Virol 60 1055 1061

19. CarswellS

ResnickJ

AlwineJC

1986 Construction and characterization of CV-1P cell lines which constitutively express the simian virus 40 agnoprotein: alteration of plaquing phenotype of viral agnogene mutants. J Virol 60 415 422

20. OkadaY

SawaH

EndoS

OrbaY

UmemuraT

2002 Expression of JC virus agnoprotein in progressive multifocal leukoencephalopathy brain. Acta Neuropathol (Berl) 104 130 136

21. RessetarHG

WalkerDL

WebsterHD

BraunDG

StonerGL

1990 Immunolabeling of JC virus large T antigen in neonatal hamster brain before tumor formation. Lab Invest 62 287 296

22. OkadaY

SuzukiT

SundenY

OrbaY

KoseS

2005 Dissociation of heterochromatin protein 1 from lamin B receptor induced by human polyomavirus agnoprotein: role in nuclear egress of viral particles. EMBO Rep 6 452 457

23. SuzukiT

OkadaY

SembaS

OrbaY

YamanouchiS

2005 Identification of FEZ1 as a protein that interacts with JC virus agnoprotein and microtubules: role of agnoprotein-induced dissociation of FEZ1 from microtubules in viral propagation. J Biol Chem 280 24948 24956

24. SariyerIK

AkanI

PalermoV

GordonJ

KhaliliK

2006 Phosphorylation mutants of JC virus agnoprotein are unable to sustain the viral infection cycle. J Virol 80 3893 3903

25. OrbaY

SawaH

IwataH

TanakaS

NagashimaK

2004 Inhibition of virus production in JC virus-infected cells by postinfection RNA interference. J Virol 78 7270 7273

26. MatobaT

OrbaY

SuzukiT

MakinoY

ShichinoheH

2008 An siRNA against JC virus (JCV) agnoprotein inhibits JCV infection in JCV-producing cells inoculated in nude mice. Neuropathology 28 286 294

27. OkadaY

EndoS

TakahashiH

SawaH

UmemuraT

2001 Distribution and function of JCV agnoprotein. J Neurovirol 7 302 306

28. GeeGV

TsomaiaN

MierkeDF

AtwoodWJ

2004 Modeling a sialic acid binding pocket in the external loops of JC virus VP1. J Biol Chem 279 49172 49176

29. BordierC

1981 Phase separation of integral membrane proteins in Triton X-114 solution. J Biol Chem 256 1604 1607

30. NagayaH

WadaI

JiaYJ

KanohH

2002 Diacylglycerol kinase delta suppresses ER-to-Golgi traffic via its SAM and PH domains. Mol Biol Cell 13 302 316

31. TekirianTL

2002 The central role of the trans-Golgi network as a gateway of the early secretory pathway: physiologic vs nonphysiologic protein transit. Exp Cell Res 281 9 18

32. SpiessM

1995 Heads or tails–what determines the orientation of proteins in the membrane. FEBS Lett 369 76 79

33. HartmannE

RapoportTA

LodishHF

1989 Predicting the orientation of eukaryotic membrane-spanning proteins. Proc Natl Acad Sci U S A 86 5786 5790

34. LelkesPI

BachD

MillerIR

1980 Perturbations of membrane structure by optical probes: II. Differential scanning calorimetry of dipalmitoyllecithin and its analogs interacting with Merocyanine 540. J Membr Biol 54 141 148

35. WilliamsonP

MattocksK

SchlegelRA

1983 Merocyanine 540, a fluorescent probe sensitive to lipid packing. Biochim Biophys Acta 732 387 393

36. StillwellW

WassallSR

DumaualAC

EhringerWD

BrowningCW

1993 Use of merocyanine (MC540) in quantifying lipid domains and packing in phospholipid vesicles and tumor cells. Biochim Biophys Acta 1146 136 144

37. DoedensJR

KirkegaardK

1995 Inhibition of cellular protein secretion by poliovirus proteins 2B and 3A. Embo J 14 894 907

38. NagaiT

YamadaS

TominagaT

IchikawaM

MiyawakiA

2004 Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins. Proc Natl Acad Sci U S A 101 10554 10559

39. DanielsR

SadowiczD

HebertDN

2007 A very late viral protein triggers the lytic release of SV40. PLoS Pathog 3 e98 doi:10.1371/journal.ppat.0030098

40. Wilson-AshworthHA

BahmQ

EricksonJ

ShinkleA

VuMP

2006 Differential detection of phospholipid fluidity, order, and spacing by fluorescence spectroscopy of bis-pyrene, prodan, nystatin, and merocyanine 540. Biophys J 91 4091 4101

41. DanielsR

RusanNM

WilbuerAK

NorkinLC

WadsworthP

2006 Simian virus 40 late proteins possess lytic properties that render them capable of permeabilizing cellular membranes. J Virol 80 6575 6587

42. MargolskeeRF

NathansD

1983 Suppression of a VP1 mutant of simian virus 40 by missense mutations in serine codons of the viral agnogene. J Virol 48 405 409

43. KhaliliK

WhiteMK

SawaH

NagashimaK

SafakM

2005 The agnoprotein of polyomaviruses: a multifunctional auxiliary protein. J Cell Physiol 204 1 7

44. GasparovicML

GeeGV

AtwoodWJ

2006 JC virus minor capsid proteins Vp2 and Vp3 are essential for virus propagation. J Virol 80 10858 10861

45. NukuzumaS

YogoY

GuoJ

NukuzumaC

ItohS

1995 Establishment and characterization of a carrier cell culture producing high titres of polyoma JC virus. J Med Virol 47 370 377

46. AshokA

AtwoodWJ

2003 Contrasting roles of endosomal pH and the cytoskeleton in infection of human glial cells by JC virus and simian virus 40. J Virol 77 1347 1356

47. SuzukiS

SawaH

KomagomeR

OrbaY

YamadaM

2001 Broad distribution of the JC virus receptor contrasts with a marked cellular restriction of virus replication. Virology 286 100 112

48. SundenY

SuzukiT

OrbaY

UmemuraT

AsamotoM

2006 Characterization and application of polyclonal antibodies that specifically recognize JC virus large T antigen. Acta Neuropathol (Berl) 111 379 387

49. LiC

HaoM

CaoZ

DingW

Graves-DealR

2007 Naked2 Acts as a Cargo Recognition and Targeting Protein to Ensure Proper Delivery and Fusion of TGF-{alpha} containing Exocytic Vesicles at the Lower Lateral Membrane of Polarized MDCK Cells. Mol Biol Cell 18 3081 3093

50. GemelJ

ValiunasV

BrinkPR

BeyerEC

2004 Connexin43 and connexin26 form gap junctions, but not heteromeric channels in co-expressing cells. J Cell Sci 117 2469 2480

51. Lopez-GimenezJF

CanalsM

PedianiJD

MilliganG

2007 The alpha1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function. Mol Pharmacol 71 1015 1029

52. OhbaY

KurokawaK

MatsudaM

2003 Mechanism of the spatio-temporal regulation of Ras and Rap1. Embo J 22 859 869

53. KomagomeR

SawaH

SuzukiT

SuzukiY

TanakaS

2002 Oligosaccharides as receptors for JC virus. J Virol 76 12992 13000

54. KyteJ

DoolittleRF