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NF-κB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance

Nature Immunology volume 13, pages 379–386 (2012)Cite this article

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Abstract

Tolerance to endotoxins that is triggered by prior exposure to Toll-like receptor (TLR) ligands provides a mechanism with which to dampen inflammatory cytokines. The receptor-interacting protein RIP140 interacts with the transcription factor NF-κB to regulate the expression of genes encoding proinflammatory cytokines. Here we found lipopolysaccharide stimulation of kinase Syk–mediated tyrosine phosphorylation of RIP140 and interaction of the NF-κB subunit RelA with RIP140. These events resulted in more recruitment of the E3 ligase SCF to tyrosine-phosphorylated RIP140, which degraded RIP140 to inactivate genes encoding inflammatory cytokines. Macrophages expressing nondegradable RIP140 were resistant to the establishment of endotoxin tolerance for specific 'tolerizable' genes. Our results identify RelA as an adaptor with which SCF fine tunes NF-κB target genes by targeting the coactivator RIP140 and show an unexpected role for RIP140 degradation in resolving inflammation and endotoxin tolerance.

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Figure 1: Exposure to TLR ligands results in less RIP140 in macrophages in vitro and in vivo.
Figure 2: LPS promotes RIP140 degradation through K48-linked polyubiquitination mediated by the SOCS1-Rbx1 E3 ligase.
Figure 3: RelA acts as adaptor for the SCF ubiquitin ligase complex to trigger degradation of RIP140.
Figure 4: Syk activity is required for LPS-induced degradation of RIP140.
Figure 5: LPS-induced degradation of RIP140 depends on Syk-mediated tyrosine-phosphorylation of RIP140.
Figure 6: Degradation of RIP140 is involved in the establishment of endotoxin tolerance.
Figure 7: Prevention of RIP140 degradation retains RelA binding and results in more active histone modification on the promoters of genes expressed in tolerant cells.

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References

  1. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. O'Neill, L.A. When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. Immunity 29, 12–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Baker, R.G., Hayden, M.S. & Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab. 13, 11–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wen, H. et al. Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10, 36–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Sheedy, F.J. et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11, 141–147 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Mansell, A. et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat. Immunol. 7, 148–155 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Foster, S.L., Hargreaves, D.C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Chen, J. & Ivashkiv, L.B. IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc. Natl. Acad. Sci. USA 107, 19438–19443 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Biswas, S.K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Park, S.H., Park-Min, K.H., Chen, J., Hu, X. & Ivashkiv, L.B. Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. Nat. Immunol. 12, 607–615 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chan, C., Li, L., McCall, C.E. & Yoza, B.K. Endotoxin tolerance disrupts chromatin remodeling and NF-κB transactivation at the IL-1β promoter. J. Immunol. 175, 461–468 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. White, R. et al. Role of RIP140 in metabolic tissues: connections to disease. FEBS Lett. 582, 39–45 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Fritah, A., Christian, M. & Parker, M.G. The metabolic coregulator RIP140: an update. Am. J. Physiol. Endocrinol. Metab. 299, E335–E340 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, C.H., Chinpaisal, C. & Wei, L.N. Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol. Cell. Biol. 18, 6745–6755 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl. Acad. Sci. USA 101, 8437–8442 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Christian, M. et al. RIP140-targeted repression of gene expression in adipocytes. Mol. Cell. Biol. 25, 9383–9391 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ho, P.C., Lin, Y.W., Tsui, Y.C., Gupta, P. & Wei, L.N. A negative regulatory pathway of GLUT4 trafficking in adipocyte: new function of RIP140 in the cytoplasm via AS160. Cell Metab. 10, 516–523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ho, P.C., Chuang, Y.S., Hung, C.H. & Wei, L.N. Cytoplasmic receptor-interacting protein 140 (RIP140) interacts with perilipin to regulate lipolysis. Cell. Signal. 23, 1396–1403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ho, P.C. & Wei, L.N. Negative regulation of adiponectin secretion by receptor interacting protein 140 (RIP140). Cell Signal. 24, 71–76 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Mostaqul Huq, M.D., Gupta, P. & Wei, L.N. Post-translational modifications of nuclear co-repressor RIP140: a therapeutic target for metabolic diseases. Curr. Med. Chem. 15, 386–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Huq, M.D., Ha, S.G., Barcelona, H. & Wei, L.N. Lysine methylation of nuclear co-repressor receptor interacting protein 140. J. Proteome Res. 8, 1156–1167 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gupta, P. et al. PKCɛ stimulated arginine methylation of RIP140 for its nuclear-cytoplasmic export in adipocyte differentiation. PLoS ONE 3, e2658 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ho, P.C. et al. Modulation of lysine acetylation-stimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation. Cell. Signal. 20, 1911–1919 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zschiedrich, I. et al. Coactivator function of RIP140 for NFκB/RelA-dependent cytokine gene expression. Blood 112, 264–276 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Ho, P.C., Chang, K.C., Chuang, Y.S. & Wei, L.N. Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. FASEB J. 25, 1758–1766 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Clague, M.J. & Urbe, S. Ubiquitin: same molecule, different degradation pathways. Cell 143, 682–685 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Natoli, G. & Chiocca, S. Nuclear ubiquitin ligases, NF-κB degradation, and the control of inflammation. Sci. Signal. 1, pe1 (2008).

    Article  PubMed  Google Scholar 

  30. Maine, G.N., Mao, X., Komarck, C.M. & Burstein, E. COMMD1 promotes the ubiquitination of NF-κB subunits through a cullin-containing ubiquitin ligase. EMBO J. 26, 436–447 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Freudenberg, M.A. & Galanos, C. Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages. Infect. Immun. 56, 1352–1357 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Vats, D. et al. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677–687 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Dimitriou, I.D. et al. Putting out the fire: coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins. Immunol. Rev. 224, 265–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Hamerman, J.A., Tchao, N.K., Lowell, C.A. & Lanier, L.L. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat. Immunol. 6, 579–586 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Hu, X., Chakravarty, S.D. & Ivashkiv, L.B. Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol. Rev. 226, 41–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Smale, S.T. Selective transcription in response to an inflammatory stimulus. Cell 140, 833–844 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Strebovsky, J., Walker, P., Lang, R. & Dalpke, A.H. Suppressor of cytokine signaling 1 (SOCS1) limits NFκB signaling by decreasing p65 stability within the cell nucleus. FASEB J. 25, 863–874 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Yoon, C.H., Miah, M.A., Kim, K.P. & Bae, Y.S. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 11, 393–399 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoo, Y., Ho, H.J., Wang, C. & Guan, J.L. Tyrosine phosphorylation of cofilin at Y68 by v-Src leads to its degradation through ubiquitin-proteasome pathway. Oncogene 29, 263–272 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Oeckinghaus, A., Hayden, M.S. & Ghosh, S. Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12, 695–708 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Wei, L.N., Hu, X., Chandra, D., Seto, E. & Farooqui, M. Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing. J. Biol. Chem. 275, 40782–40787 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Vo, N., Fjeld, C. & Goodman, R.H. Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. Mol. Cell. Biol. 21, 6181–6188 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rao, M.K. & Wilkinson, M.F. Tissue-specific and cell type-specific RNA interference in vivo. Nat. Protoc. 1, 1494–1501 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank P.-T. Liu, S.C. Chan, K.-C. Chang, Y.-S. Chuang, A. Smith, C. Korteum and P. Lam for technical help and S. Kaech for critical reading. Supported by US National Insitutes of Health (DK60521, DK54733, DA11190 and K02-DA13926), the Distinguished McKnigh Professorship of the University of of Minnesota (L.-N. Wei) and the American Heart Association (P.-C. Ho).

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  1. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    Ping-Chih Ho, Yao-Chen Tsui, Xudong Feng & Li-Na Wei

  2. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    David R Greaves

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P.-C.H. designed and did most experiments and wrote the manuscript; Y.-C.T. did animal experiments and analyzed the results; X.F. did animal experiments; D.R.G. provided reagents; and L.-N.W. supervised and analyzed the research, wrote the manuscript and provided financial support.

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Correspondence to Li-Na Wei.

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Ho, PC., Tsui, YC., Feng, X. et al. NF-κB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 13, 379–386 (2012). https://doi.org/10.1038/ni.2238

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