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

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.

[1]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[2]  E. Fisher,et al.  TLR signaling and trapped vascular dendritic cells in the development of atherosclerosis. , 2006, Trends in immunology.

[3]  S. Fields,et al.  Binding specificity of Toll‐like receptor cytoplasmic domains , 2006, European journal of immunology.

[4]  J. Bartek,et al.  The Stress of Finding NEMO , 2006, Science.

[5]  G. Pei,et al.  Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling , 2006, Nature Immunology.

[6]  L. O’Neill,et al.  How Toll-like receptors signal: what we know and what we don't know. , 2006, Current opinion in immunology.

[7]  Paul J Hertzog,et al.  Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation , 2006, Nature Immunology.

[8]  M. Mann,et al.  Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 , 2006, Nature.

[9]  A. Dunne,et al.  New insights into the post-translational modification of Toll-like receptor signaling molecules , 2005, Journal of endotoxin research.

[10]  S. Su,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 , 2005, The Journal of Immunology.

[11]  R. Alsabeh,et al.  MyD88 Is Pivotal for the Early Inflammatory Response and Subsequent Bacterial Clearance and Survival in a Mouse Model of Chlamydia pneumoniae Pneumonia* , 2005, Journal of Biological Chemistry.

[12]  Zhijian J. Chen.  Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[13]  F. Liew,et al.  Negative regulation of Toll-like receptor-mediated immune responses , 2005, Nature Reviews Immunology.

[14]  M. Kitagawa,et al.  Transcriptional induction of Smurf2 ubiquitin ligase by TGF‐β , 2005, FEBS letters.

[15]  A. Marshak‐Rothstein,et al.  Toll‐like receptors, endogenous ligands, and systemic autoimmune disease , 2005, Immunological reviews.

[16]  Makoto Nakanishi,et al.  A20 Is a Negative Regulator of IFN Regulatory Factor 3 Signaling1 , 2005, The Journal of Immunology.

[17]  L. Cantley,et al.  The Crohn's Disease Protein, NOD2, Requires RIP2 in Order to Induce Ubiquitinylation of a Novel Site on NEMO , 2004, Current Biology.

[18]  M. Arditi,et al.  TB, or not TB: that is the question -- does TLR signaling hold the answer? , 2004, The Journal of clinical investigation.

[19]  A. Amerik,et al.  Mechanism and function of deubiquitinating enzymes. , 2004, Biochimica et biophysica acta.

[20]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[21]  P. Shah,et al.  TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis1 , 2004, The Journal of Immunology.

[22]  Matthew T Wheeler,et al.  The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses , 2004, Nature Immunology.

[23]  C. Coban,et al.  Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 , 2004, Nature Immunology.

[24]  D. Schwartz,et al.  Toll-like receptors in the pathogenesis of human disease , 2004, Nature Immunology.

[25]  A. Iwasaki,et al.  Toll-like receptor control of the adaptive immune responses , 2004, Nature Immunology.

[26]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[27]  Tomohiro Watanabe,et al.  NOD2 is a negative regulator of Toll-like receptor 2–mediated T helper type 1 responses , 2004, Nature Immunology.

[28]  D. Wallach.  Faculty Opinions recommendation of De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. , 2004 .

[29]  P. Hertzog,et al.  Mal Interacts with Tumor Necrosis Factor Receptor-associated Factor (TRAF)-6 to mediate NF-κB Activation by Toll-like Receptor (TLR)-2 and TLR4* , 2004, Journal of Biological Chemistry.

[30]  B. Beutler,et al.  Inferences, questions and possibilities in Toll-like receptor signalling , 2004, Nature.

[31]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[32]  Zhijian J. Chen,et al.  The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. , 2004, Molecular cell.

[33]  Y. Shoenfeld,et al.  Toll-like Receptors and their Role in the Development of Autoimmune Diseases , 2004, Autoimmunity.

[34]  R. Ulevitch,et al.  Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors , 2004, Nature Immunology.

[35]  M. Guenounou,et al.  Toll-like receptors and immune response in allergic disease , 2004, Clinical reviews in allergy & immunology.

[36]  M. Sweet,et al.  T1/ST2--an IL-1 receptor-like modulator of immune responses. , 2004, Cytokine & growth factor reviews.

[37]  L. Attisano,et al.  Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation , 2004, Oncogene.

[38]  Honglin Zhou,et al.  Bcl10 activates the NF-κB pathway through ubiquitination of NEMO , 2004, Nature.

[39]  C. Heldin,et al.  Ecsit-ement on the crossroads of Toll and BMP signal transduction. , 2003, Genes & development.

[40]  B. Hogan,et al.  Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. , 2003, Genes & development.

[41]  Masato Kubo,et al.  Suppressors of cytokine signaling and immunity , 2003, Nature Immunology.

[42]  S. Miyamoto,et al.  Sequential Modification of NEMO/IKKγ by SUMO-1 and Ubiquitin Mediates NF-κB Activation by Genotoxic Stress , 2003, Cell.

[43]  J. Arron,et al.  TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[44]  A. Whitehead,et al.  Ubiquitin activated tumor necrosis factor receptor associated factor‐6 (TRAF6) is recycled via deubiquitination , 2003, FEBS letters.

[45]  G. Stark,et al.  SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling , 2003, Nature Immunology.

[46]  D. Kuhns,et al.  Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections , 2003, The Journal of experimental medicine.

[47]  J. Tschopp,et al.  MyD88S, a splice variant of MyD88, differentially modulates NF‐κB‐ and AP‐1‐dependent gene expression , 2003, FEBS letters.

[48]  T. Blundell,et al.  A Novel Type of Deubiquitinating Enzyme* , 2003, Journal of Biological Chemistry.

[49]  S. Akira,et al.  Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. , 2003, The Journal of clinical investigation.

[50]  Ivan Dikic,et al.  Negative receptor signalling. , 2003, Current opinion in cell biology.

[51]  G. Strous,et al.  Dimerization, ubiquitylation and endocytosis go together in growth hormone receptor function , 2002, FEBS letters.

[52]  T. Asano,et al.  PI3K-mediated negative feedback regulation of IL-12 production in DCs , 2002, Nature Immunology.

[53]  Charles A. Janeway,et al.  IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling , 2002, Cell.

[54]  T. Mak,et al.  Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 , 2002, Nature.

[55]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[56]  J. Tschopp,et al.  Regulation of Interleukin-1- and Lipopolysaccharide-Induced NF-κB Activation by Alternative Splicing of MyD88 , 2002, Current Biology.

[57]  Sankar Ghosh,et al.  Negative Regulation of Toll-like Receptor-mediated Signaling by Tollip* , 2002, The Journal of Biological Chemistry.

[58]  C. Heldin,et al.  Smad regulation in TGF-beta signal transduction. , 2001, Journal of cell science.

[59]  E. R. Taylor,et al.  Isolation and characterization of two novel A20-like proteins. , 2001, The Biochemical journal.

[60]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[61]  Zhijian J. Chen,et al.  TAK1 is a ubiquitin-dependent kinase of MKK and IKK , 2001, Nature.

[62]  Judy H. Cho,et al.  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease , 2001, Nature.

[63]  Tomoki Chiba,et al.  Smurf1 Interacts with Transforming Growth Factor-β Type I Receptor through Smad7 and Induces Receptor Degradation* , 2001, The Journal of Biological Chemistry.

[64]  S. Yamaoka,et al.  Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB* , 2001, The Journal of Biological Chemistry.

[65]  R. Derynck,et al.  Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  J. Wrana,et al.  Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. , 2000, Molecular cell.

[67]  Xia Lin,et al.  Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-β Signaling* 210 , 2000, The Journal of Biological Chemistry.

[68]  R. Beyaert,et al.  A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. , 2000, Biochemical pharmacology.

[69]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[70]  S. Ghosh,et al.  Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex , 2000 .

[71]  F. Martinon,et al.  Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor , 2000, Nature Cell Biology.

[72]  H. Lodish,et al.  Role of transforming growth factor beta in human disease. , 2000, The New England journal of medicine.

[73]  C. Janeway,et al.  ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. , 1999, Genes & development.

[74]  S. Wasserman,et al.  Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. , 1999, Journal of immunology.

[75]  J. Sims,et al.  Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. , 1999, Cytokine.

[76]  V. Dixit,et al.  RIP2 Is a Novel NF-κB-activating and Cell Death-inducing Kinase* , 1998, The Journal of Biological Chemistry.

[77]  G. Courtois,et al.  Complementation Cloning of NEMO, a Component of the IκB Kinase Complex Essential for NF-κB Activation , 1998, Cell.

[78]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[79]  R. C. Walsh,et al.  Sequence and structure of the Drosophila melanogaster ovarian tumor gene and generation of an antibody specific for the ovarian tumor protein , 1989, Molecular and cellular biology.

[80]  J. Bartek,et al.  Cell biology. The stress of finding NEMO. , 2006, Science.

[81]  Zhijian J. Chen.  Ubiquitin signalling in the NF-kappaB pathway. , 2005, Nature cell biology.

[82]  K. Michelsen,et al.  Transforming Growth Factor-β Differentially Inhibits MyD88-dependent, but Not TRAM- and TRIF-dependent, Lipopolysaccharide-induced TLR4 Signaling* , 2005, Journal of Biological Chemistry.

[83]  Honglin Zhou,et al.  Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. , 2004, Nature.

[84]  L. Lenz,et al.  TRAIL-R as a negative regulator of innate immune cell responses. , 2004, Immunity.

[85]  Zhijian J. Chen,et al.  TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[86]  S. Miyamoto,et al.  Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. , 2003, Cell.

[87]  C. Pickart,et al.  Mechanisms underlying ubiquitination. , 2001, Annual review of biochemistry.

[88]  J. Pober,et al.  Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. , 2000, Science.

[89]  V. Dixit,et al.  RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. , 1998, The Journal of biological chemistry.

[90]  G. Courtois,et al.  Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. , 1998, Cell.

[91]  C. Janeway.  Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.