#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Upregulation of xCT by KSHV-Encoded microRNAs Facilitates KSHV Dissemination and Persistence in an Environment of Oxidative Stress


Upregulation of xCT, the inducible subunit of a membrane-bound amino acid transporter, replenishes intracellular glutathione stores to maintain cell viability in an environment of oxidative stress. xCT also serves as a fusion-entry receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS). Ongoing KSHV replication and infection of new cell targets is important for KS progression, but whether xCT regulation within the tumor microenvironment plays a role in KS pathogenesis has not been determined. Using gene transfer and whole virus infection experiments, we found that KSHV-encoded microRNAs (KSHV miRNAs) upregulate xCT expression by macrophages and endothelial cells, largely through miR-K12-11 suppression of BACH-1—a negative regulator of transcription recognizing antioxidant response elements within gene promoters. Correlative functional studies reveal that upregulation of xCT by KSHV miRNAs increases cell permissiveness for KSHV infection and protects infected cells from death induced by reactive nitrogen species (RNS). Interestingly, KSHV miRNAs simultaneously upregulate macrophage secretion of RNS, and biochemical inhibition of RNS secretion by macrophages significantly reduces their permissiveness for KSHV infection. The clinical relevance of these findings is supported by our demonstration of increased xCT expression within more advanced human KS tumors containing a larger number of KSHV-infected cells. Collectively, these data support a role for KSHV itself in promoting de novo KSHV infection and the survival of KSHV-infected, RNS-secreting cells in the tumor microenvironment through the induction of xCT.


Vyšlo v časopise: Upregulation of xCT by KSHV-Encoded microRNAs Facilitates KSHV Dissemination and Persistence in an Environment of Oxidative Stress. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000742
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000742

Souhrn

Upregulation of xCT, the inducible subunit of a membrane-bound amino acid transporter, replenishes intracellular glutathione stores to maintain cell viability in an environment of oxidative stress. xCT also serves as a fusion-entry receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS). Ongoing KSHV replication and infection of new cell targets is important for KS progression, but whether xCT regulation within the tumor microenvironment plays a role in KS pathogenesis has not been determined. Using gene transfer and whole virus infection experiments, we found that KSHV-encoded microRNAs (KSHV miRNAs) upregulate xCT expression by macrophages and endothelial cells, largely through miR-K12-11 suppression of BACH-1—a negative regulator of transcription recognizing antioxidant response elements within gene promoters. Correlative functional studies reveal that upregulation of xCT by KSHV miRNAs increases cell permissiveness for KSHV infection and protects infected cells from death induced by reactive nitrogen species (RNS). Interestingly, KSHV miRNAs simultaneously upregulate macrophage secretion of RNS, and biochemical inhibition of RNS secretion by macrophages significantly reduces their permissiveness for KSHV infection. The clinical relevance of these findings is supported by our demonstration of increased xCT expression within more advanced human KS tumors containing a larger number of KSHV-infected cells. Collectively, these data support a role for KSHV itself in promoting de novo KSHV infection and the survival of KSHV-infected, RNS-secreting cells in the tumor microenvironment through the induction of xCT.


Zdroje

1. LuppiM

BarozziP

SchulzTF

SettiG

StaskusK

2000 Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med 343 1378 1385

2. SoulierJ

GrolletL

OksenhendlerE

CacoubP

Cazals-HatemD

1995 Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86 1276 1280

3. CesarmanE

ChangY

MoorePS

SaidJW

KnowlesDM

1995 Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332 1186 1191

4. ChangY

CesarmanE

PessinMS

LeeF

CulpepperJ

1994 Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266 1865 1869

5. EngelsEA

BiggarRJ

HallHI

CrossH

CrutchfieldA

2008 Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 123 187 194

6. BonnetF

LewdenC

MayT

HeripretL

JouglaE

2004 Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer 101 317 324

7. LebbeC

LegendreC

FrancesC

2008 Kaposi sarcoma in transplantation. Transplant Rev (Orlando) 22 252 261

8. ShepherdFA

MaherE

CardellaC

ColeE

GreigP

1997 Treatment of Kaposi's sarcoma after solid organ transplantation. J Clin Oncol 15 2371 2377

9. Cook-MozaffariP

NewtonR

BeralV

BurkittDP

1998 The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic. Br J Cancer 78 1521 1528

10. VanniT

SprinzE

MachadoMW

Santana RdeC

FonsecaBA

2006 Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives. Cancer Treat Rev 32 445 455

11. MaurerT

PonteM

LeslieK

2007 HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N Engl J Med 357 1352 1353

12. KrownSE

LeeJY

DittmerDP

2008 More on HIV-associated Kaposi's sarcoma. N Engl J Med 358 535 536; author reply 536

13. Von RoennJH

2003 Clinical presentations and standard therapy of AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am 17 747 762

14. SchulzTF

2006 The pleiotropic effects of Kaposi's sarcoma herpesvirus. J Pathol 208 187 198

15. CampbellTB

BorokM

GwanzuraL

MaWhinneyS

WhiteIE

2000 Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage. AIDS 14 2109 2116

16. QuinlivanEB

ZhangC

StewartPW

KomoltriC

DavisMG

2002 Elevated virus loads of Kaposi's sarcoma-associated human herpesvirus 8 predict Kaposi's sarcoma disease progression, but elevated levels of human immunodeficiency virus type 1 do not. J Infect Dis 185 1736 1744

17. DupinN

FisherC

KellamP

AriadS

TulliezM

1999 Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A 96 4546 4551

18. KedesDH

GanemD

1997 Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest 99 2082 2086

19. MartinDF

KuppermannBD

WolitzRA

PalestineAG

LiH

1999 Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med 340 1063 1070

20. LambertM

GannageM

KarrasA

AbelM

LegendreC

2006 Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma. Blood 108 3871 3880

21. BihlF

MosamA

HenryLN

ChisholmJV3rd

DollardS

2007 Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma. AIDS 21 1245 1252

22. GrundhoffA

GanemD

2004 Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest 113 124 136

23. LebbeC

de CremouxP

MillotG

PodgorniakMP

VerolaO

1997 Characterization of in vitro culture of HIV-negative Kaposi's sarcoma-derived cells. In vitro responses to alfa interferon. Arch Dermatol Res 289 421 428

24. TsuchiyaS

KobayashiY

GotoY

OkumuraH

NakaeS

1982 Induction of maturation in cultured human monocytic leukemia cells by a phorbol diester. Cancer Res 42 1530 1536

25. LoM

WangYZ

GoutPW

2008 The x(c)- cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215 593 602

26. KaleebaJA

BergerEA

2006 Kaposi's sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science 311 1921 1924

27. VeettilMV

SadagopanS

Sharma-WaliaN

WangFZ

RaghuH

2008 Kaposi's sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the post entry stage of infection. J Virol 82 12126 12144

28. SirianniMC

VincenziL

FiorelliV

TopinoS

ScalaE

UcciniS

AngeloniA

FaggioniA

CerimeleD

CottoniF

AiutiF

EnsoliB

Gamma-interferon production in peripheral blood mononuclear cells and tumor infiltrating lymphocytes from Kaposi's sarcoma patients: correlation with the presence of human herpesvirus-8 in peripheral blood monocytes and lesional macrophages. Blood 1998; 91(3) 968 76

29. RappoccioloG

JenkinsFJ

HenslerHR

PiazzaP

JaisM

2006 DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J Immunol 176 1741 1749

30. GanemD

ZiegelbauerJ

2008 MicroRNAs of Kaposi's sarcoma-associated herpes virus. Semin Cancer Biol 18 437 440

31. CaiX

LuS

ZhangZ

GonzalezCM

DamaniaB

2005 Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci U S A 102 5570 5575

32. SamolsMA

HuJ

SkalskyRL

RenneR

2005 Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi's sarcoma-associated herpesvirus. J Virol 79 9301 9305

33. PfefferS

SewerA

Lagos-QuintanaM

SheridanR

SanderC

2005 Identification of microRNAs of the herpesvirus family. Nat Methods 2 269 276

34. SasakiH

SatoH

Kuriyama-MatsumuraK

SatoK

MaebaraK

2002 Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277 44765 44771

35. IshiiT

ItohK

TakahashiS

SatoH

YanagawaT

2000 Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275 16023 16029

36. SkalskyRL

SamolsMA

PlaisanceKB

BossIW

RivaA

2007 Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol 81 12836 12845

37. DhakshinamoorthyS

JainAK

BloomDA

JaiswalAK

2005 Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280 16891 16900

38. DhakshinamoorthyS

JaiswalAK

2002 c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction. Oncogene 21 5301 5312

39. HongYK

ForemanK

ShinJW

HirakawaS

CurryCL

2004 Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36 683 685

40. RodriguezA

VigoritoE

ClareS

WarrenMV

CouttetP

2007 Requirement of bic/microRNA-155 for normal immune function. Science 316 608 611

41. ParsonsCH

AdangLA

OverdevestJ

O'ConnorCM

TaylorJR,Jr.

2006 KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice. J Clin Invest 116 1963 1973

42. GoutPW

KangYJ

BuckleyDJ

BruchovskyN

BuckleyAR

1997 Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells. Leukemia 11 1329 1337

43. GoutPW

SimmsCR

RobertsonMC

2003 In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine. Anticancer Drugs 14 21 29

44. SamolsMA

SkalskyRL

MaldonadoAM

RivaA

LopezMC

2007 Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3 e65 doi:10.1371/journal.ppat.0030065

45. GuidarelliA

ScioratiC

ClementiE

CantoniO

2006 Peroxynitrite mobilizes calcium ions from ryanodine-sensitive stores, a process associated with the mitochondrial accumulation of the cation and the enforced formation of species mediating cleavage of genomic DNA. Free Radic Biol Med 41 154 164

46. FreyRS

Ushio-FukaiM

MalikA

2009 NADPH Oxidase-Dependent Signaling in Endothelial Cells: Role in Physiology and Pathophysiology. Antioxid Redox Signal 11 791 810

47. LambethJD

2004 NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4 181 189

48. AsehnouneK

StrassheimD

MitraS

KimJY

AbrahamE

2004 Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J Immunol 172 2522 2529

49. LeeSJ

KimKM

NamkoongS

KimCK

KangYC

2005 Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. J Biol Chem 280 5781 5788

50. MallerySR

PeiP

LandwehrDJ

ClarkCM

BradburnJE

2004 Implications for oxidative and nitrative stress in the pathogenesis of AIDS-related Kaposi's sarcoma. Carcinogenesis 25 597 603

51. AlexanderJH

ReynoldsHR

StebbinsAL

DzavikV

HarringtonRA

2007 Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA 297 1657 1666

52. PakF

PyakuralP

KokhaeiP

KaayaE

PourfathollahAA

2005 HHV-8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry. J Cutan Pathol 32 21 27

53. PyakurelP

MassambuC

Castanos-VelezE

EricssonS

KaayaE

2004 Human herpesvirus 8/Kaposi sarcoma herpesvirus cell association during evolution of Kaposi sarcoma. J Acquir Immune Defic Syndr 36 678 683

54. GillPS

TsaiYC

RaoAP

SpruckCH3rd

ZhengT

1998 Evidence for multiclonality in multicentric Kaposi's sarcoma. Proc Natl Acad Sci U S A 95 8257 8261

55. StaskusKA

ZhongW

GebhardK

HerndierB

WangH

1997 Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71 715 719

56. BoulangerE

DuprezR

DelabesseE

GabarreJ

MacintyreE

2005 Mono/oligoclonal pattern of Kaposi Sarcoma-associated herpesvirus (KSHV/HHV-8) episomes in primary effusion lymphoma cells. Int J Cancer 115 511 518

57. AdangLA

TomescuC

LawWK

KedesDH

2007 Intracellular Kaposi's sarcoma-associated herpesvirus load determines early loss of immune synapse components. J Virol 81 5079 5090

58. BabcockGJ

DeckerLL

FreemanRB

Thorley-LawsonDA

1999 Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J Exp Med 190 567 576

59. AdangLA

ParsonsCH

KedesDH

2006 Asynchronous progression through the lytic cascade and variations in intracellular viral loads revealed by high-throughput single-cell analysis of Kaposi's sarcoma-associated herpesvirus infection. J Virol 80 10073 10082

60. ZhuJ

LiS

MarshallZM

WhortonAR

2008 A cystine-cysteine shuttle mediated by xCT facilitates cellular responses to S-nitrosoalbumin. Am J Physiol Cell Physiol 294 C1012 1020

61. McAllisterSC

HansenSG

RuhlRA

RaggoCM

DeFilippisVR

2004 Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood 103 3465 3473

62. WeningerW

RendlM

PammerJ

MildnerM

TschugguelW

1998 Nitric oxide synthases in Kaposi's sarcoma are expressed predominantly by vessels and tissue macrophages. Lab Invest 78 949 955

63. PyoCW

LeeSH

ChoiSY

2008 Oxidative stress induces PKR-dependent apoptosis via IFN-gamma activation signaling in Jurkat T cells. Biochem Biophys Res Commun 377 1001 1006

64. YanagisawaN

ShimadaK

MiyazakiT

KumeA

KitamuraY

2008 Enhanced production of nitric oxide, reactive oxygen species, and pro-inflammatory cytokines in very long chain saturated fatty acid-accumulated macrophages. Lipids Health Dis 7 48

65. KimSY

KimTB

MoonKA

KimTJ

ShinD

2008 Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo. Exp Mol Med 40 461 476

66. MaQ

CavallinLE

YanB

ZhuS

DuranEM

2009 Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc Natl Acad Sci U S A 106 8683 8688

67. ThurauM

MarquardtG

Gonin-LaurentN

WeinlanderK

NaschbergerE

2009 Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death. J Virol 83 598 611

68. YuJY

ChungKH

DeoM

ThompsonRC

TurnerDL

2008 MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Exp Cell Res 314 2618 2633

69. TomescuC

LawWK

KedesDH

2003 Surface downregulation of major histocompatibility complex class I, PE-CAM, and ICAM-1 following de novo infection of endothelial cells with Kaposi's sarcoma-associated herpesvirus. J Virol 77 9669 9684

70. TsutsumiS

ScrogginsB

KogaF

LeeMJ

TrepelJ

2008 A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 27 2478 2487

71. GraysonW

PantanowitzL

2008 Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol 3 31

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
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

#ADS_BOTTOM_SCRIPTS#