Review: Ubiquitination and de-ubiquitination: role in regulation of signaling by Toll-like receptors

Abstract

Signaling by Toll-like receptors (TLRs) has attracted accelerating attention over the past decade because of the central role of TLR signaling in both innate and adaptive immunity. In addition, TLR signaling is now increasingly implicated in a remarkably wide range of diseases that are either caused, or accompanied, by dysregulated inflammation. Much has been learned about the basic signaling framework and participants, as well as how signaling is turned off and fine-tuned. Here, we summarize key aspects of TLR signaling, focusing on interaction with the anti-inflammatory TGF-β signaling network. We propose that ubiquitination and de-ubiquitination of TLR pathway components may be a mechanism by which predominantly anti-inflammatory input is integrated into the host response to fine-tune inflammation in accordance with the needs of host defenses.

Keywords

De-ubiquitination inflammation innate immunity Toll-like receptor ubiquitin

References

Janeway Jr CA Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989; 54: 1—13.

Akira S. , Takeda K. , Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity . Nat Immunol 2001; 2: 675—680.

Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling . Nature 2004; 430: 257—263.

Iwasaki A. , Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5: 987—995.

Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001; 1: 135—145.

O'Neill Laj. How Toll-like receptors signal: what we know and what we don't know. Curr Opin Immunol 2005; 17: 1—7.

Doherty TM , Fisher EA , Arditi M. TLR signaling and trapped vascular dendritic cells in the development of atherosclerosis . Trends Immunol 2006; 27: 222—227.

Doherty TM , Arditi M. TB, or not TB: that is the question — does TLR signaling hold the answer ? J Clin Invest 2004; 114: 1699—1703.

Michelsen KS , Doherty TM , Shah PK , Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 2004; 173: 5901—5907.

10.

Cook DN , Pisetsky DS , Schwartz DA Toll-like receptors in the pathogenesis of human disease. Nat Immunol 2004; 5: 975—979.

11.

Gangloff SC , Guenounou M. Toll-like receptors and immune response in allergic disease. Clin Rev Allergy Immunol 2004; 26: 115—125.

12.

Goldstein DR , Tesar BM , Akira S. , Lakkis FG Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest 2003; 111: 1571—1578.

13.

Rifkin IR , Leadbetter EA , Busconi L. , Viglianti G. , Marshak-Rothstein A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 2005; 204: 27—42.

14.

Su SB , Silver PB , Grajewski RS et al. Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity . J Immunol 2005; 175: 6303—6310.

15.

Toubi E. , Shoenfeld Y. Toll-like receptors and their role in the development of autoimmune diseases . Autoimmunity 2004; 37: 183—188.

16.

Liew FY , Xu D. , Brint EK , O'Neill LA Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol 2005; 5: 446—458.

17.

Takeda K. , Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17: 1—14.

18.

Naiki Y. , Michelsen KS , Schröder NW et al. MyD88 is pivotal for the early inflammatory response and subsequent bacterial clearance and survival in a mouse model of Chlamydia pneumoniae pneumonia. J Biol Chem 2005; 280: 29242—29249.

19.

Brown V. , Brown RA , Ozinsky A. , Hesselberth JR , Fields S. Binding specificity of Toll-like receptor cytoplasmic domains. Eur J Immunol 2006; 36: 742—753.

20.

Dunne A. , O'Neill L. New insights into the post-translational modification of Toll-like receptor signaling molecules. J Endotoxin Res 2005; 11: 325—332.

21.

Akira S. , Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4: 499—511.

22.

Hacker H. , Redecke V. , Blagoev B. et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 2006; 439: 204—207.

23.

Kawai T. , Sato S. , Ishii KJ et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 2004; 5: 1061—1068.

24.

Thomassen E. , Renshaw BR , Sims JE Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 1999; 11: 389—399.

25.

Trajkovic V. , Sweet MJ , Xu D. T1/ST2 — an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev 2004; 15: 87—95.

26.

Wald D. , Qin J. , Zhao Z. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 2003; 4: 920—927.

27.

Diehl GE , Yue HH , Hsieh K. et al. TRAIL-R as a negative regulator of innate immune cell responses . Immunity 2004; 21: 877—889.

28.

Kobayashi K. , Hernandez LD , Galan JE , Janeway Jr CA, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002; 110: 191—202.

29.

Janssens S. , Burns K. , Tschopp J. , Beyaert R. Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88. Curr Biol 2002; 12: 467—471.

30.

Janssens S. , Burns K. , Vercammen E. , Tschopp J. , Beyaert R. MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett 2003; 548: 103—107.

31.

Burns K. , Clatworthy J. , Martin L. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2000; 2: 346—351.

32.

Zhang G. , Ghosh S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002; 277: 7059—7065.

33.

Fukao T. , Tanabe M. , Terauchi Y. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol 2002; 3: 875—881.

34.

Watanabe T. , Kitani A. , Murray PJ , Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004; 5: 800—808.

35.

Abbott DW , Wilkins A. , Asara JM , Cantley LC The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 2004; 14: 2217—2227.

36.

Wang Y. , Tang Y. , Teng L. , Wu Y. , Zhao X. , Pei G. Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 2006; 7: 139—147.

37.

Dikic I. , Giordano S. Negative receptor signalling. Curr Opin Cell Biol 2003; 15: 128—135.

38.

Glickman MH , Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002; 82: 373—428.

39.

Pickart CM Mechanisms underlying ubiquitination. Annu Rev Biochem 2001; 70: 503—533.

40.

Strous GJ , Gent J. Dimerization, ubiquitylation and endocytosis go together in growth hormone receptor function. FEBS Lett 2002; 529: 102—109.

41.

Weissman AM Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2001; 2: 169—178.

42.

Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2001; 2: 195—201.

43.

Suzuki N. , Suzuki S. , Duncan GS et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002; 416: 750—756.

44.

Thomas JA , Allen JL , Tsen M. et al. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J Immunol 1999; 163: 978—984.

45.

Medvedev AE , Lentschat A. , Kuhns DB et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003; 198: 521—531.

46.

Wu H. , Arron JR TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays 2003; 25: 1096—1105.

47.

Deng L. , Wang C. , Spencer E. et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain . Cell 2000; 103: 351—361.

48.

Ea CK , Sun L. , Inoue J. , Chen ZJ

TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Proc Natl Acad

Sci USA 2004; 101: 15318—15323.

49.

Sun L. , Deng L. , Ea CK , Xia ZP , Chen ZJ The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 2004; 14: 289—301.

50.

Wang C. , Deng L. , Hong M. , Akkaraju GR , Inoue J. , Chen ZJ TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412: 346—351.

51.

Chen ZJ Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 2005; 7: 758—765.

52.

Amerik AY , Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 2004; 1695: 189—207.

53.

Beyaert R. , Heyninck K. , Van Huffel S. A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. Biochem Pharmacol 2000; 60: 1143—1151.

54.

Jensen LE , Whitehead AS Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination. FEBS Lett 2003; 553: 190—194.

55.

Boone DL , Turer EE , Lee EG et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004; 5: 1052—1060.

56.

Saitoh T. , Yamamoto M. , Miyagishi M. et al. A20 is a negative regulator of IFN regulatory factor 3 signaling . J Immunol 2005; 174: 1507—1512.

57.

Wertz IE , O'Rourke KM , Zhou H. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430: 694—699.

58.

Bartek J. , Lukas J. Cell biology. The stress of finding NEMO. Science 2006; 311: 1110—1111.

59.

Huang TT , Wuerzberger-Davis SM , Wu ZH , Miyamoto S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 2003; 115: 565—576.

60.

May MJ , D'Acquisto F. , Madge LA , Glockner J. , Pober JS , Ghosh S. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 2000; 289: 1550—1554.

61.

Yamaoka S. , Courtois G. , Bessia C. et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 1998; 93: 1231—1240.

62.

Zhou H. , Wertz I. , O'Rourke K. et al. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 2004; 427: 167—171.

63.

Ogura Y. , Inohara N. , Benito A. , Chen FF , Yamaoka S. , Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001; 276: 4812—4818.

64.

McCarthy JV , Ni J. , Dixit VM RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem 1998; 273: 16968—16975.

65.

Ogura Y. , Bonen DK , Inohara N. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603—606.

66.

Chuang TH , Ulevitch RJ Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 2004; 5: 495—502.

67.

Evans PC , Taylor ER , Coadwell J. , Heyninck K. , Beyaert R. , Kilshaw PJ Isolation and characterization of two novel A20-like proteins. Biochem J 2001; 357: 617—623.

68.

Evans PC , Smith TS , Lai MJ et al. A novel type of deubiquitinating enzyme. J Biol Chem 2003; 278: 23180—23186.

69.

Steinhauer WR , Walsh RC , Kalfayan LJ Sequence and structure of the Drosophila melanogaster ovarian tumor gene and generation of an antibody specific for the ovarian tumor protein. Mol Cell Biol 1989; 9: 5726—5732.

70.

Ebisawa T. , Fukuchi M. , Murakami G. et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 2001; 276: 12477—12480.

71.

Izzi L. , Attisano L. Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation . Oncogene 2004; 23: 2071—2078.

72.

Kavsak P. , Rasmussen RK , Causing CG et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-beta receptor for degradation. Mol Cell 2000; 6: 1365—1375.

73.

Lin X. , Liang M. , Feng XH Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 2000; 275: 36818—36822.

74.

Zhang Y. , Chang C. , Gehling DJ , Hemmati-Brivanlou A. , Derynck R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase . Proc Natl Acad Sci USA 2001; 98: 974—979.

75.

Ohashi N. , Yamamoto T. , Uchida C. et al. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta . FEBS Lett 2005; 579: 2557—2563.

76.

Blobe GC , Schiemann WP , Lodish HF Role oftransforming growth factor beta in human disease. N Engl J Med 2000; 342: 1350—1358.

77.

Shull MM , Ormsby I. , Kier AB et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359: 693—699.

78.

Naiki Y. , Michelsen KS , Zhang W. , Chen S. , Doherty TM , Arditi M. Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. J Biol Chem 2005; 280: 5491—5495.

79.

Moustakas A. , Heldin CH Ecsit-ement on the crossroads of Toll and BMP signal transduction. Genes Dev 2003; 17: 2855—2859.

80.

Xiao C. , Shim JH , Kluppel M. et al. Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes Dev 2003; 17: 2933—2949.

81.

Moustakas A. , Souchelnytskyi S. , Heldin CH Smad regulation in TGF-beta signal transduction . J Cell Sci 2001; 114: 4359—4369.

82.

Kopp E. , Medzhitov R. , Carothers J. et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 1999 ; 13: 2059—2071.

83.

Mansell A. , Brint E. , Gould JA , O'Neill LA , Hertzog PJ Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4. J Biol Chem 2004; 279: 37227—37230.

84.

Mansell A. , Smith R. , Doyle SL et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 2006; 7: 148—155.

85.

Kubo M. , Hanada T. , Yoshimura A. Suppressors of cytokine signaling and immunity. Nat Immunol 2003; 4: 1169—1176.