Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1


In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-β promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5′ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.


Vyšlo v časopise: Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1. PLoS Pathog 6(7): e32767. doi:10.1371/journal.ppat.1001012
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001012

Souhrn

In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-β promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5′ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.


Zdroje

1. SamuelCE

2001 Antiviral actions of interferons. Clin Microbiol Rev 14 778 809, table of contents

2. TheofilopoulosAN

BaccalaR

BeutlerB

KonoDH

2005 Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23 307 336

3. KotenkoSV

GallagherG

BaurinVV

Lewis-AntesA

ShenM

2003 IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4 69 77

4. SheppardP

KindsvogelW

XuW

HendersonK

SchlutsmeyerS

2003 IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 4 63 68

5. YoneyamaM

FujitaT

2009 RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227 54 65

6. OnoguchiK

YoneyamaM

TakemuraA

AkiraS

TaniguchiT

2007 Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem 282 7576 7581

7. KawaiT

TakahashiK

SatoS

CobanC

KumarH

2005 IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6 981 988

8. MeylanE

CurranJ

HofmannK

MoradpourD

BinderM

2005 Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 1167 1172

9. SethRB

SunL

EaCK

ChenZJ

2005 Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122 669 682

10. XuLG

WangYY

HanKJ

LiLY

ZhaiZ

2005 VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19 727 740

11. ArnoultD

CarneiroL

TattoliI

GirardinSE

2009 The role of mitochondria in cellular defense against microbial infection. Semin Immunol 21 223 232

12. HornungV

EllegastJ

KimS

BrzozkaK

JungA

2006 5′-Triphosphate RNA is the ligand for RIG-I. Science 314 994 997

13. PichlmairA

SchulzO

TanCP

NaslundTI

LiljestromP

2006 RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314 997 1001

14. TakahasiK

YoneyamaM

NishihoriT

HiraiR

KumetaH

2008 Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell 29 428 440

15. BenardG

KarbowskiM

2009 Mitochondrial fusion and division: Regulation and role in cell viability. Semin Cell Dev Biol 20 365 374

16. IwamuraT

YoneyamaM

KoizumiN

OkabeY

NamikiH

2001 PACT, a double-stranded RNA binding protein acts as a positive regulator for type I interferon gene induced by Newcastle disease virus. Biochem Biophys Res Commun 282 515 523

17. YoneyamaM

KikuchiM

NatsukawaT

ShinobuN

ImaizumiT

2004 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5 730 737

18. SantelA

FrankS

GaumeB

HerrlerM

YouleRJ

2003 Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci 116 2763 2774

19. ChenH

DetmerSA

EwaldAJ

GriffinEE

FraserSE

2003 Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160 189 200

20. CipolatS

Martins de BritoO

Dal ZilioB

ScorranoL

2004 OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101 15927 15932

21. IshiharaN

NomuraM

JofukuA

KatoH

SuzukiSO

2009 Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11 958 966

22. YoneyamaM

KikuchiM

MatsumotoK

ImaizumiT

MiyagishiM

2005 Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175 2851 2858

23. MooreCB

BergstralhDT

DuncanJA

LeiY

MorrisonTE

2008 NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451 573 577

24. TangED

WangCY

2009 MAVS self-association mediates antiviral innate immune signaling. J Virol 83 3420 3428

25. YasukawaK

OshiumiH

TakedaM

IshiharaN

YanagiY

2009 Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci Signal 2 ra47

26. CastanierC

GarcinD

VazquezA

ArnoultD

2010 Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep 11 133 138

27. FujitaT

2009 A nonself RNA pattern: tri-p to panhandle. Immunity 31 4 5

28. AlbertsB

JohnsonA

LewisJ

RaffM

RobertsK

2008 Energy Conversion: Mitochondria and Chloroplasts. Molecular Biology of the Cell, Fifth Edition New York Garland Science 813 878

29. YoneyamaM

SuharaW

FukuharaY

SatoM

OzatoK

1996 Autocrine amplification of type I interferon gene expression mediated by interferon stimulated gene factor 3 (ISGF3). J Biochem 120 160 169

30. KaukinenP

SillanpaaM

KotenkoS

LinR

HiscottJ

2006 Hepatitis C virus NS2 and NS3/4A proteins are potent inhibitors of host cell cytokine/chemokine gene expression. Virol J 3 66

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
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