Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action
The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling.
Vyšlo v časopise:
Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002057
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002057
Souhrn
The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling.
Zdroje
1. AkiraSUematsuSTakeuchiO 2006 Pathogen recognition and innate immunity. Cell 124 783 801
2. KawaiTAkiraS 2010 The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11 373 384
3. MedzhitovR 2007 Recognition of microorganisms and activation of the immune response. Nature 449 819 826
4. DieboldSSKaishoTHemmiHAkiraSReis e SousaC 2004 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303 1529 1531
5. HeilFHemmiHHochreinHAmpenbergerFKirschningC 2004 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303 1526 1529
6. YangKPuelAZhangSEidenschenkCKuCL 2005 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23 465 478
7. KawaiTSatoSIshiiKJCobanCHemmiH 2004 Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5 1061 1068
8. HoshinoKSugiyamaTMatsumotoMTanakaTSaitoM 2006 IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440 949 953
9. WangCDengLHongMAkkarajuGRInoueJ 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412 346 351
10. KobayashiKHernandezLDGalanJEJanewayCAJrMedzhitovR 2002 IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110 191 202
11. BrintEKXuDLiuHDunneAMcKenzieAN 2004 ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5 373 379
12. WaldDQinJZhaoZQianYNaramuraM 2003 SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4 920 927
13. NakagawaRNakaTTsutsuiHFujimotoMKimuraA 2002 SOCS-1 participates in negative regulation of LPS responses. Immunity 17 677 687
14. LeeEGBooneDLChaiSLibbySLChienM 2000 Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289 2350 2354
15. WertzIEO'RourkeKMZhouHEbyMAravindL 2004 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430 694 699
16. WilkinsonKD 2003 Signal transduction: aspirin, ubiquitin and cancer. Nature 424 738 739
17. RotheMXiongJShuHBWilliamsonKGoddardA 1996 I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction. Proc Natl Acad Sci U S A 93 8241 8246
18. ChengGBaltimoreD 1996 TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-kappaB activation. Genes Dev 10 963 973
19. KawagoeTTakeuchiOTakabatakeYKatoHIsakaY 2009 TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol 10 965 972
20. ScottI 2009 Mitochondrial factors in the regulation of innate immunity. Microbes Infect 11 729 736
21. ZhongBYangYLiSWangYYLiY 2008 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29 538 550
22. OnoguchiKOnomotoKTakamatsuSJogiMTakemuraA 2010 Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1. PLoS Pathog 6 e1001012
23. MooreCBBergstralhDTDuncanJALeiYMorrisonTE 2008 NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451 573 577
24. IshikawaHBarberGN 2008 STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455 674 678
25. LinRPazSHiscottJ 2010 Tom70 imports antiviral immunity to the mitochondria. Cell Res 20 971 973
26. LiuXYWeiBShiHXShanYFWangC 2010 Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. Cell Res 20 994 1011
27. YangKShiHXQiRSunSGTangYJ 2006 Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Molecular Biology of the Cell 17 1461 1471
28. WangXHerrRAHansenT 2008 Viral and cellular MARCH ubiquitin ligases and cancer. Semin Cancer Biol 18 441 450
29. KarbowskiMNeutznerAYouleRJ 2007 The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178 71 84
30. NakamuraNKimuraYTokudaMHondaSHiroseS 2006 MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7 1019 1022
31. YonashiroRIshidoSKyoSFukudaTGotoE 2006 A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J 25 3618 3626
32. YouFSunHZhouXSunWLiangS 2009 PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol 10 1300 1308
33. PazSVilascoMArguelloMSunQLacosteJ 2009 Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter. Mol Cell Biol 29 3401 3412
34. ArimotoKTakahashiHHishikiTKonishiHFujitaT 2007 Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A 104 7500 7505
35. GatotJSGioiaRChauTLPatrascuFWarnierM 2007 Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. J Biol Chem 282 31131 31146
36. GuoBChengG 2007 Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK. J Biol Chem 282 11817 11826
37. WangCChenTZhangJYangMLiN 2009 The E3 ubiquitin ligase Nrdp1 ‘preferentially’ promotes TLR-mediated production of type I interferon. Nat Immunol 10 744 752
38. KayagakiNPhungQChanSChaudhariRQuanC 2007 DUBA: a deubiquitinase that regulates type I interferon production. Science 318 1628 1632
39. DengLWangCSpencerEYangLBraunA 2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103 351 361
40. YangKZhuJSunSTangYZhangB 2004 The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination. Biochem Biophys Res Commun 324 432 439
41. HochstrasserM 2006 Lingering mysteries of ubiquitin-chain assembly. Cell 124 27 34
42. KoeglMHoppeTSchlenkerSUlrichHDMayerTU 1999 A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96 635 644
43. IwaiKTokunagaF 2009 Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep 10 706 713
44. HackerHRedeckeVBlagoevBKratchmarovaIHsuLC 2006 Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439 204 207
45. BlasiusALBeutlerB 2010 Intracellular toll-like receptors. Immunity 32 305 315
46. ShiHXYangKLiuXLiuXYWeiB 2010 Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol 30 2424 2436
47. CareyKDGartonAJRomeroMSKahlerJThomsonS 2006 Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res 66 8163 8171
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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