Loss of Trabid, a New Negative Regulator of the Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span

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A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalling. Moreover, Lysine at position 156 functioned as a K48-linked Ubiquitin acceptor site, also necessary for TAK1 activity. The deubiquitinase Trabid interacted with TAK1, reducing immune signalling output and K63-linked ubiquitination. The three tandem Npl4 Zinc Fingers and the catalytic Cysteine at position 518 were required for Trabid activity. Flies deficient for Trabid had a reduced life span due to chronic activation of IMD both systemically as well as in their gut where homeostasis was disrupted. The TAK1-associated Binding Protein 2 (TAB2) was linked with the TAK1-Trabid interaction through its Zinc finger domain that pacified the TAK1 signal. These results indicate an elaborate and multi-tiered mechanism for regulating TAK1 activity and modulating its immune signal.

Vyšlo v časopise: Loss of Trabid, a New Negative Regulator of the Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004117
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004117

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Zdroje

1. HoellerD, DikicI (2009) Targeting the ubiquitin system in cancer therapy. Nature 458: 438–444.

2. KomanderD (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37: 937–953.

3. ChenJ, Chen ZJ (2013) Regulation of NF-κB by ubiquitination. Curr Op Immunol 25 (1) 4–12.

4. KounatidisI, LigoxygakisP (2012) Drosophila as a model system to unravel the layers of innate immunity to infection. Open Biology 2: 120075.

5. KanekoT, YanoT, AggarwalK, LimJH, UedaK, et al. (2006) PGRP-LC and PGRP-LE have essential yet distinct func- tions in the drosophila immune response to monomeric DAP-type peptidoglycan. Nat Immunol 7: 715–723.

6. GeorgelP, NaitzaS, KapplerC, FerrandonD, ZacharyD, et al. (2001) Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev Cell 1: 503–514.

7. LeulierF, VidalS, SaigoK, UedaR, LemaitreB (2002) Inducible expression of double-stranded RNA reveals a role for dFADD in the regulation of the antibacterial response in Drosophila adults. Curr Biol 12: 996–1000.

8. NaitzaS, RosséC, KapplerC, GeorgelP, BelvinM, et al. (2002) The Drosophila immune defense against gram-negative infection requires the death protein dFADD. Immunity 17: 575–81.

9. LeulierF, RodriguezA, KhushRS, AbramsJM, LemaitreB (2000) The Drosophila caspase Dredd is required to resist gram-negative bacterial infection. EMBO Rep 1: 353–358.

10. MeinanderA, RunchelC, TenevT, ChenL, KimC-H, et al. (2012) Ubiquitylation of the initiator caspase DREDD is required for innate immune signalling. EMBO J 31: 2770–83.

11. PaquetteN, BroemerM, AggarwalK, ChenL, HussonM, et al. (2010) Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling. Mol Cell 37: 172–82.

12. VidalS, KhushRS, LeulierF, TzouP, NakamuraM, et al. (2001) Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-kappaB-dependent innate immune responses. Genes & Dev 15: 1900–1912.

13. KleinoA, ValanneS, UlvilaJ, KallioJ, MyllymakiH, et al. (2005) Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway. EMBO J 24: 3423–3434.

14. SilvermanN, ZhouR, ErlichRL, HunterM, BernsteinE, et al. (2003) Immune Activation of NF-κB and JNK Requires Drosophila TAK1. J Biol Chem 278: 48928–48934.

15. Erturk-HasdemirD, BroemerM, LeulierF, LaneWS, PaquetteN, et al. (2009) Two roles for the Drosophila IKK complex in the activation of Relish and the induction of antimicrobial peptide genes. Proc Natl Acad Sci USA 106: 9779–9784.

16. StovenS, AndoI, KadalayilL, EngstromY, HultmarkD (2000) Activation of the Drosophila NF-kappaB factor Relish by rapid endoproteolytic cleavage. EMBO Rep 1: 347–352.

17. LemaitreB, ReichhartJ-M, HoffmannJA (1997) Drosophila host defense: Differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc Natl Acad Sci USA 94: 14614–14619.

18. ParedesJC, WelchmanDP, PoidevinM (2011) LemaitreB (2011) Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35: 770–9.

19. KleinoA, MyllymäkiH, KallioJ, Vanha-ahoL-M, OksanenK, et al. (2008) Pirk is a negative regulator of the Drosophila Imd pathway. J Immunol 180: 5413–22.

20. AggarwalK, RusF, Vriesema-MagnusonC, Ertürk-HasdemirD, PaquetteN, et al. (2008) Rudra interrupts receptor signalling complexes to negatively regulate the IMD pathway. PLoS Path 4: e1000120.

21. LhocineN, RibeiroPS, BuchonN, WepfA, WilsonR, et al. (2008) PIMS modulates immune tolerance by negatively regulating Drosophila innate immune signaling. Cell Host Microbe 4: 147–58.

22. ThevenonD, EngelE, Avet-RochexA, GottarM, BergeretE, et al. (2009) The Drosophila ubiquitin-specific protease dUSP36/Scny targets IMD to prevent constitutive immune signaling. Cell Host Microbe 6: 309–20.

23. TsichritzisT, GaentzschPC, KosmidisS, BrownAE, SkoulakisEM, et al. (2007) A Drosophila ortholog of the human cylindromatosis tumor suppressor gene regulates triglyceride content and antibacterial defence. Development 134: 2605–2614.

24. ParkJM, BradyH, RuoccoMG, SunH, WilliamsD, et al. (2004) Targeting of TAK1 by the NF-kappa B protein Relish regulates the JNK-mediated immune response in Drosophila. Genes Dev 18: 584–594.

25. ZhouR, SilvermanN, HongM, LiaoDS, ChungY, et al. (2005) The role of ubiquitination in Drosophila innate immu- nity. J Biol Chem 280: 34048–34055.

26. FanY, YuY, ShiY, SunW, XieM, et al. (2010) Lysine 63-linked Polyubiquitination of TAK1 at Lysine 158 Is Required for Tumor Necrosis Factor (alpha)- and Interleukin-1(beta)-induced IKK/NF-kappaB and JNK/AP-1 Activation. J Biol Chem 285: 5347–5360.

27. FanY, YuY, MaoR, ZhangH, YangJ (2011) TAK1 Lys-158 but not Lys-209 is required for IL-1[beta]-induced Lys63-linked TAK1 polyubiquitination and IKK/NF-κB activation. Cell Signalling 23: 660–665.27.

28. HeyninckK, BeyaertR (1999) The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-κB activation at the level of TRAF6. FEBS Letters 442: 147–150.

29. VereeckeL, BeyaertR, van LooG (2009) The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 30: 383–391.

30. TranH, HamadaF, Schwarz-RomondT, BienzM (2008) Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains. Genes Dev 22: 528–542.

31. BellenHJ, LevisRW, LiaoG, HeY, CarlsonJW, et al. (2004) The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167: 761–781.

32. DantoftW, DavisMM, LindvallJM, TangX, UvellA, et al. (2013) The Oct1 homolog Nubbin is a repressor of NF-κB-dependent immune gene expression that increases the tolerance to gut microbiota. BMC Biol 11: 99–118.

33. BuchonN, BroderickNA, ChakrabartiS, LemaitreB (2009) Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev 23: 2333–44.

34. JiangH, PatelPH, KohmaierA, GrenleyMO, McEwenDG, et al. (2009) Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137: 1343–55.

35. ZhouF, RasmussenA, LeeS, AgaisseH (2013) The UPD3 cytokine couples environmental challenge and intestinal stem cell division through modulation of JAK/STAT signaling in the stem cell microenvironment. Dev Biol 373: 383–93.

36. BalakirevMY, TcherniukSO, JaquinodM, ChroboczekJ (2003) Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Rep 4: 517–522.

37. TsudaM, LangmannC, HardenN (2005) AigakiT (2005) The RING-finger scaffold protein Plenty of SH3s targets TAK1 to control immunity signalling in Drosophila. EMBO Rep 6: 1082–7.

38. LiangL, FanY, ChengJ, ChengD, ZhaoY, et al. (2013) TAK1 ubiquitination regulates doxorubicin-induced NF-κB activation. Cell Signalling 25: 247–54.

39. FanY, ShiY, LiuS, MaoR, AnL, et al. (2012) Lys48-linked TAK1 polyubiquitination at lysine-72 down-regulates TNFα-induced NF-κB activation via mediating TAK1 degradation,. Cell Signalling 24: 1381–1389.

40. IshitaniT, TakaesuG, Ninomiya-TsujiJ, ShibuyaH, GaynorRB, et al. (2003) Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J 22: 6277–6288.

41. BesseA, LamotheB, CamposAD, WebsterWK, MaddineniU, et al. (2007) TAK1-dependent Signaling Requires Functional Interaction with TAB2/TAB3. J Biol Chem 282: 3918–3928.

42. KanayamaA, SethRB, SunL, EaC-K, HongM, et al. (2004) TAB2 and TAB3 Activate the NF-[kappa]B Pathway through Binding to Polyubiquitin Chains. Mol Cell 15: 535–548.

43. DelaneyJ, StovenS, UvellH, AndersonK, EngstromY, et al. (2006) Cooperative control of Drosophila immune responses by the JNK and NF-kappaB signalling pathways. EMBO J 25: 3068–3077.

44. LiuS, ChenZJ (2011) Expanding role of ubiquitination in NF-κB signaling. Cell Res 21: 6–21.

45. CarterRS, PenningtonKN, ArrateP, OltzEM, BallardDW (2005) Site-specific Monoubiquitination of I-kappa-B Kinase IKK-beta Regulates Its Phosphorylation and Persistent Activation. J Biol Chem 280: 43272–43279.

46. BonnayF, Cohen-BerrosE, HoffmannM, KimSY, BoulianneGL, et al. (2013) big bang gene modulates gut immune tolerance in Drosophila. Proc Natl Acad Sci USA 110: 2957–296.

47. HarhajEW, DixitVM (2012) Regulation of NF-kB by deubiquitinases. Immunol Rev 246: 107–124.

48. ShinSC, KimSH, YouH, KimB, KimAC, et al. (2011) Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signalling. Science 6056: 670–4.

49. GlittenbergMT, SilasS, MacCallumDM, GowNA, LigoxygakisP (2011) Wild-type Drosophila melanogaster as an alternative model system for investigating the pathogenicity of Candida albicans. Dis Model Mech 4: 504–14.