Ubiquitin-Regulated Nuclear-Cytoplasmic Trafficking of the Nipah Virus Matrix Protein Is Important for Viral Budding

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Paramyxoviruses are known to replicate in the cytoplasm and bud from the plasma membrane. Matrix is the major structural protein in paramyxoviruses that mediates viral assembly and budding. Curiously, the matrix proteins of a few paramyxoviruses have been found in the nucleus, although the biological function associated with this nuclear localization remains obscure. We report here that the nuclear-cytoplasmic trafficking of the Nipah virus matrix (NiV-M) protein and associated post-translational modification play a critical role in matrix-mediated virus budding. Nipah virus (NiV) is a highly pathogenic emerging paramyxovirus that causes fatal encephalitis in humans, and is classified as a Biosafety Level 4 (BSL4) pathogen. During live NiV infection, NiV-M was first detected in the nucleus at early stages of infection before subsequent localization to the cytoplasm and the plasma membrane. Mutations in the putative bipartite nuclear localization signal (NLS) and the leucine-rich nuclear export signal (NES) found in NiV-M impaired its nuclear-cytoplasmic trafficking and also abolished NiV-M budding. A highly conserved lysine residue in the NLS served dual functions: its positive charge was important for mediating nuclear import, and it was also a potential site for monoubiquitination which regulates nuclear export of the protein. Concordantly, overexpression of ubiquitin enhanced NiV-M budding whereas depletion of free ubiquitin in the cell (via proteasome inhibitors) resulted in nuclear retention of NiV-M and blocked viral budding. Live Nipah virus budding was exquisitely sensitive to proteasome inhibitors: bortezomib, an FDA-approved proteasome inhibitor for treating multiple myeloma, reduced viral titers with an IC₅₀ of 2.7 nM, which is 100-fold less than the peak plasma concentration that can be achieved in humans. This opens up the possibility of using an “off-the-shelf” therapeutic against acute NiV infection.

Vyšlo v časopise: Ubiquitin-Regulated Nuclear-Cytoplasmic Trafficking of the Nipah Virus Matrix Protein Is Important for Viral Budding. PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001186
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001186

Souhrn

Zdroje

1. EatonBT

BroderCC

MiddletonD

WangLF

2006 Hendra and Nipah viruses: different and dangerous. Nat Rev Microbiol 4 23 35

2. FieldH

YoungP

YobJM

MillsJ

HallL

2001 The natural history of Hendra and Nipah viruses. Microbes Infect 3 307 314

3. ChuaKB

BelliniWJ

RotaPA

HarcourtBH

TaminA

2000 Nipah virus: a recently emergent deadly paramyxovirus. Science 288 1432 1435

4. WeingartlHM

BerhaneY

CzubM

2009 Animal models of henipavirus infection: a review. Vet J 181 211 220

5. HsuVP

HossainMJ

ParasharUD

AliMM

KsiazekTG

2004 Nipah virus encephalitis reemergence, Bangladesh. Emerg Infect Dis 10 2082 2087

6. 2009 ProMED-mail PRO/AH/EDR> Hendra virus, human, equine - Australia (04): (QL) fatal. 20090903.3098

7. LambRA

ParksGD

2006 Paramyxoviridae: The Viruses and Their Replication.

KnipeDM

HowleyPM

Fields Virology. Fifth ed Philadelphia Lippincott, Williams and Wilkins 1449 1496

8. TakimotoT

PortnerA

2004 Molecular mechanism of paramyxovirus budding. Virus Res 106 133 145

9. GaroffH

HewsonR

OpsteltenDJ

1998 Virus maturation by budding. Microbiol Mol Biol Rev 62 1171 1190

10. CiancanelliMJ

BaslerCF

2006 Mutation of YMYL in the Nipah virus matrix protein abrogates budding and alters subcellular localization. J Virol 80 12070 12078

11. 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

12. PatchJR

HanZ

McCarthySE

YanL

WangLF

2008 The YPLGVG sequence of the Nipah virus matrix protein is required for budding. Virol J 5 137

13. ShawML

CardenasWB

ZamarinD

PaleseP

BaslerCF

2005 Nuclear localization of the Nipah virus W protein allows for inhibition of both virus- and toll-like receptor 3-triggered signaling pathways. J Virol 79 6078 6088

14. ShawML

Garcia-SastreA

PaleseP

BaslerCF

2004 Nipah virus V and W proteins have a common STAT1-binding domain yet inhibit STAT1 activation from the cytoplasmic and nuclear compartments, respectively. J Virol 78 5633 5641

15. CiancanelliMJ

VolchkovaVA

ShawML

VolchkovVE

BaslerCF

2009 Nipah virus sequesters inactive STAT1 in the nucleus via a P gene-encoded mechanism. J Virol 83 7828 7841

16. WatanabeN

KawanoM

TsurudomeM

KusagawaS

NishioM

1996 Identification of the sequences responsible for nuclear targeting of the V protein of human parainfluenza virus type 2. J Gen Virol 77 Pt 2 327 338

17. YoshidaT

Nagai Y'YoshiiS

MaenoK

MatsumotoT

1976 Membrane (M) protein of HVJ (Sendai virus): its role in virus assembly. Virology 71 143 161

18. ColemanNA

PeeplesME

1993 The matrix protein of Newcastle disease virus localizes to the nucleus via a bipartite nuclear localization signal. Virology 195 596 607

19. PeeplesME

WangC

GuptaKC

ColemanN

1992 Nuclear entry and nucleolar localization of the Newcastle disease virus (NDV) matrix protein occur early in infection and do not require other NDV proteins. J Virol 66 3263 3269

20. PeeplesME

1988 Differential detergent treatment allows immunofluorescent localization of the Newcastle disease virus matrix protein within the nucleus of infected cells. Virology 162 255 259

21. GhildyalR

HoA

DiasM

SoegiyonoL

BardinPG

2009 The respiratory syncytial virus matrix protein possesses a Crm1-mediated nuclear export mechanism. J Virol 83 5353 5362

22. GhildyalR

HoA

WagstaffKM

DiasMM

BartonCL

2005 Nuclear import of the respiratory syncytial virus matrix protein is mediated by importin beta1 independent of importin alpha. Biochemistry 44 12887 12895

23. GhildyalR

Baulch-BrownC

MillsJ

MeangerJ

2003 The matrix protein of Human respiratory syncytial virus localises to the nucleus of infected cells and inhibits transcription. Arch Virol 148 1419 1429

24. FaabergKS

PeeplesME

1988 Strain variation and nuclear association of Newcastle disease virus matrix protein. J Virol 62 586 593

25. KanwalC

LiH

LimCS

2002 Model system to study classical nuclear export signals. AAPS PharmSci 4 E18

26. TerryLJ

ShowsEB

WenteSR

2007 Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science 318 1412 1416

27. DingwallC

LaskeyRA

1991 Nuclear targeting sequences–a consensus? Trends Biochem Sci 16 478 481

28. EfthymiadisA

ShaoH

HubnerS

JansDA

1997 Kinetic characterization of the human retinoblastoma protein bipartite nuclear localization sequence (NLS) in vivo and in vitro. A comparison with the SV40 large T-antigen NLS. J Biol Chem 272 22134 22139

29. SchlenstedtG

1996 Protein import into the nucleus. FEBS Lett 389 75 79

30. FukudaM

AsanoS

NakamuraT

AdachiM

YoshidaM

1997 CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 390 308 311

31. KauTR

WayJC

SilverPA

2004 Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer 4 106 117

32. LohrumMA

WoodsDB

LudwigRL

BalintE

VousdenKH

2001 C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 21 8521 8532

33. LiM

BrooksCL

Wu-BaerF

ChenD

BaerR

2003 Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302 1972 1975

34. TrotmanLC

WangX

AlimontiA

ChenZ

Teruya-FeldsteinJ

2007 Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128 141 156

35. ShcherbikN

HainesDS

2004 Ub on the move. J Cell Biochem 93 11 19

36. HuangTT

Wuerzberger-DavisSM

WuZH

MiyamotoS

2003 Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 115 565 576

37. RandowF

LehnerPJ

2009 Viral avoidance and exploitation of the ubiquitin system. Nat Cell Biol 11 527 534

38. IsaacsonMK

PloeghHL

2009 Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe 5 559 570

39. HendersonBR

EleftheriouA

2000 A comparison of the activity, sequence specificity, and CRM1-dependence of different nuclear export signals. Exp Cell Res 256 213 224

40. PankivS

LamarkT

BruunJA

OvervatnA

BjorkoyG

2010 Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J Biol Chem 285 5941 5953

41. LiSY

DavidsonPJ

LinNY

PattersonRJ

WangJL

2006 Transport of galectin-3 between the nucleus and cytoplasm. II. Identification of the signal for nuclear export. Glycobiology 16 612 622

42. RodriguezJJ

CruzCD

HorvathCM

2004 Identification of the nuclear export signal and STAT-binding domains of the Nipah virus V protein reveals mechanisms underlying interferon evasion. J Virol 78 5358 5367

43. PatnaikA

ChauV

WillsJW

2000 Ubiquitin is part of the retrovirus budding machinery. Proc Natl Acad Sci U S A 97 13069 13074

44. SchubertU

OttDE

ChertovaEN

WelkerR

TessmerU

2000 Proteasome inhibition interferes with gag polyprotein processing, release, and maturation of HIV-1 and HIV-2. Proc Natl Acad Sci U S A 97 13057 13062

45. VogtVM

2000 Ubiquitin in retrovirus assembly: actor or bystander? Proc Natl Acad Sci U S A 97 12945 12947

46. MoritaE

SundquistWI

2004 Retrovirus budding. Annu Rev Cell Dev Biol 20 395 425

47. HoellerD

CrosettoN

BlagoevB

RaiborgC

TikkanenR

2006 Regulation of ubiquitin-binding proteins by monoubiquitination. Nat Cell Biol 8 163 169

48. QianSB

OttDE

SchubertU

BenninkJR

YewdellJW

2002 Fusion proteins with COOH-terminal ubiquitin are stable and maintain dual functionality in vivo. J Biol Chem 277 38818 38826

49. CarterS

BischofO

DejeanA

VousdenKH

2007 C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 9 428 435

50. LeeJC

WangGX

SchicklingO

PeterME

2005 Fusing DEDD with ubiquitin changes its intracellular localization and apoptotic potential. Apoptosis 10 1483 1495

51. SpearmanP

WangJJ

Vander HeydenN

RatnerL

1994 Identification of human immunodeficiency virus type 1 Gag protein domains essential to membrane binding and particle assembly. J Virol 68 3232 3242

52. Hermida-MatsumotoL

ReshMD

2000 Localization of human immunodeficiency virus type 1 Gag and Env at the plasma membrane by confocal imaging. J Virol 74 8670 8679

53. RodgersW

2002 Making membranes green: construction and characterization of GFP-fusion proteins targeted to discrete plasma membrane domains. Biotechniques 32 1044 1046, 1048, 1050–1041

54. Shenoy-ScariaAM

GauenLK

KwongJ

ShawAS

LublinDM

1993 Palmitylation of an amino-terminal cysteine motif of protein tyrosine kinases p56lck and p59fyn mediates interaction with glycosyl-phosphatidylinositol-anchored proteins. Mol Cell Biol 13 6385 6392

55. ElliottPJ

ZollnerTM

BoehnckeWH

2003 Proteasome inhibition: a new anti-inflammatory strategy. J Mol Med 81 235 245

56. Sanchez-SerranoI

2006 Success in translational research: lessons from the development of bortezomib. Nat Rev Drug Discov 5 107 114

57. PapandreouCN

DalianiDD

NixD

YangH

MaddenT

2004 Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22 2108 2121

58. OgawaY

TobinaiK

OguraM

AndoK

TsuchiyaT

2008 Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Cancer Sci 99 140 144

59. HickeL

2001 Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2 195 201

60. JohnsonES

2002 Ubiquitin branches out. Nat Cell Biol 4 E295 298

61. TanakaT

SorianoMA

GrusbyMJ

2005 SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 22 729 736

62. NatoliG

ChioccaS

2008 Nuclear ubiquitin ligases, NF-kappaB degradation, and the control of inflammation. Sci Signal 1 pe1

63. Martin-SerranoJ

2007 The role of ubiquitin in retroviral egress. Traffic 8 1297 1303

64. SaadJS

MillerJ

TaiJ

KimA

GhanamRH

2006 Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc Natl Acad Sci U S A 103 11364 11369

65. GonzaloS

LinderME

1998 SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. Mol Biol Cell 9 585 597

66. ManieSN

de BreyneS

VincentS

GerlierD

2000 Measles virus structural components are enriched into lipid raft microdomains: a potential cellular location for virus assembly. J Virol 74 305 311

67. BrownG

RixonHW

SugrueRJ

2002 Respiratory syncytial virus assembly occurs in GM1-rich regions of the host-cell membrane and alters the cellular distribution of tyrosine phosphorylated caveolin-1. J Gen Virol 83 1841 1850

68. AliA

NayakDP

2000 Assembly of Sendai virus: M protein interacts with F and HN proteins and with the cytoplasmic tail and transmembrane domain of F protein. Virology 276 289 303

69. ReedLJ

MuenchH

1938 A simple method of estimating fifty percent endpoints. The American Journal of Hygiene 493 397

70. LimKL

ChewKC

TanJM

WangC

ChungKK

2005 Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 25 2002 2009

71. GuoX

RoldanA

HuJ

WainbergMA

LiangC

2005 Mutation of the SP1 sequence impairs both multimerization and membrane-binding activities of human immunodeficiency virus type 1 Gag. J Virol 79 1803 1812