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Klotho suppresses RIG-I-mediated senescence-associated inflammation

An Erratum to this article was published on 01 April 2011

This article has been updated


It is well known that aged or senescent cells develop a complex senescence-associated secretory phenotype (SASP), which is observed both in culture and in vivo. However, the mechanisms underlying the induction of the SASP are largely unknown. We demonstrate that retinoic-acid-inducible gene-I (RIG-I) is induced through the ataxia telangiectasia mutated–interferon regulatory factor 1 (ATM–IRF1) axis in senescent cells and that RIG-I signalling mediates the expression of two important mediators of inflammation, interleukin-6 (IL-6) and IL-8. Klotho has been associated with ageing. We show here that the intracellular, but not the secreted, form of klotho interacts with RIG-I and that this interaction inhibits RIG-I-induced expression of IL-6 and IL-8 both in vitro and in vivo. Our study uncovers a mechanism in which klotho functions as an anti-ageing factor through the suppression of RIG-I-mediated inflammation.

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Figure 1: Correlation of induction of RIG-I with interleukins, and reduction of klotho in replicative senescent cells.
Figure 2: RIG-I signalling mediates senescence-associated inflammation.
Figure 3: Endogenous klotho is a physiological inhibitor of RIG-I-mediated expression of IL-6.
Figure 4: Klotho inhibits RIG-I-mediated activation of NF-κB.
Figure 5: RIG-I-mediated expression of IL-6 and 8 is suppressed by intracellular, not secreted, klotho.
Figure 6: Inhibition of RIG-I-mediated expression of interleukins by klotho through the block of RIG-I multimerization.

Change history

  • 16 March 2011

    In the version of this article initially published online, a graph in Fig. 3b was mislabelled and there were errors in the text on pages 4 and 5 and in the figure legend for Fig. 4c.


  1. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  Google Scholar 

  2. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  Google Scholar 

  3. Wei, W., Hemmer, R. M. & Sedivy, J. M. Role of p14(ARF) in replicative and induced senescence of human fibroblasts. Mol. Cell Biol. 21, 6748–6757 (2001).

    Article  CAS  Google Scholar 

  4. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  CAS  Google Scholar 

  5. Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    CAS  PubMed  Google Scholar 

  6. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999).

    Article  CAS  Google Scholar 

  7. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    Article  CAS  Google Scholar 

  8. Sebastian, T., Malik, R., Thomas, S., Sage, J. & Johnson, P. F. C/EBPβ cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. EMBO J. 24, 3301–3312 (2005).

    Article  CAS  Google Scholar 

  9. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  Google Scholar 

  10. Nagai, T. et al. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J. 17, 50–52 (2003).

    Article  CAS  Google Scholar 

  11. Nagai, R. et al. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell. Mol. Life Sci. 57, 738–746 (2000).

    Article  CAS  Google Scholar 

  12. Saito, Y. et al. Klotho protein protects against endothelial dysfunction. Biochem. Biophys. Res. Commun. 248, 324–329 (1998).

    Article  CAS  Google Scholar 

  13. Matsumura, Y. et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem. Biophys. Res. Commun. 242, 626–630 (1998).

    Article  CAS  Google Scholar 

  14. Shiraki-Iida, T. et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 424, 6–10 (1998).

    Article  CAS  Google Scholar 

  15. Xiao, N.M., Zhang, Y.M., Zheng, Q. & Gu, J. Klotho is a serum factor related to human aging. Chin. Med. J. (Engl) 117, 742–747 (2004).

    CAS  Google Scholar 

  16. Tsujikawa, H., Kurotaki, Y., Fujimori, T., Fukuda, K. & Nabeshima, Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol. Endocrinol. 17, 2393–2403 (2003).

    Article  CAS  Google Scholar 

  17. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  Google Scholar 

  18. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  Google Scholar 

  19. Chang, Q. et al. The β-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310, 490–493 (2005).

    Article  CAS  Google Scholar 

  20. Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).

    Article  CAS  Google Scholar 

  21. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806 (2007).

    Article  CAS  Google Scholar 

  22. Ikushima, M. et al. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem. Biophys. Res. Commun. 339, 827–832 (2006).

    Article  CAS  Google Scholar 

  23. Mitobe, M. et al. Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp. Nephrol. 101, e67–e74 (2005).

    Article  CAS  Google Scholar 

  24. Yamamoto, M. et al. Regulation of oxidative stress by the anti-aging hormone klotho. J. Biol. Chem. 280, 38029–38034 (2005).

    Article  CAS  Google Scholar 

  25. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article  CAS  Google Scholar 

  26. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005).

    Article  CAS  Google Scholar 

  27. Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell. 19, 727–740 (2005).

    Article  CAS  Google Scholar 

  28. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  Google Scholar 

  29. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    Article  CAS  Google Scholar 

  30. Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

    Article  CAS  Google Scholar 

  31. Wang, J. et al. Retinoic acid-inducible gene-I mediates late phase induction of TNF-α by lipopolysaccharide. J. Immunol. 180, 8011–8019 (2008).

    Article  CAS  Google Scholar 

  32. Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 β production. Nat. Immunol. 11, 63–69 (2010).

    Article  CAS  Google Scholar 

  33. Kubota, K. et al. Retinoic acid-inducible gene-I is induced in gingival fibroblasts by lipopolysaccharide or poly IC: possible roles in interleukin-1β, -6 and -8 expression. Oral Microbiol. Immunol. 21, 399–406 (2006).

    Article  CAS  Google Scholar 

  34. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    Article  CAS  Google Scholar 

  35. Pamment, J., Ramsay, E., Kelleher, M., Dornan, D. & Ball, K. L. Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway. Oncogene 21, 7776–7785 (2002).

    Article  CAS  Google Scholar 

  36. Kawaguchi, S. et al. Retinoic acid-inducible gene-I is constitutively expressed and involved in IFN-γ-stimulated CXCL9-11 production in intestinal epithelial cells. Immunol. Lett. 123, 9–13 (2009).

    Article  CAS  Google Scholar 

  37. Imaizumi, T. et al. Retinoic acid-inducible gene-I (RIG-I) is induced by IFN-γ in human mesangial cells in culture: possible involvement of RIG-I in the inflammation in lupus nephritis. Lupus 19, 830–836 (2010).

    Article  CAS  Google Scholar 

  38. Imaizumi, T. et al. Tumor-necrosis factor-α induces retinoic acid-inducible gene-I in rheumatoid fibroblast-like synoviocytes. Immunol. Lett. 122, 89–93 (2009).

    Article  CAS  Google Scholar 

  39. Imaizumi, T. et al. Involvement of retinoic acid-inducible gene-I in inflammation of rheumatoid fibroblast-like synoviocytes. Clin. Exp. Immunol. 153, 240–244 (2008).

    Article  CAS  Google Scholar 

  40. Maekawa, Y. et al. Klotho suppresses TNF-α-induced expression of adhesion molecules in the endothelium and attenuates NF-κB activation. Endocrine 35, 341–346 (2009).

    Article  CAS  Google Scholar 

  41. Chen, C. D., Podvin, S., Gillespie, E., Leeman, S. E. & Abraham, C. R. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc. Natl Acad. Sci. USA 104, 19796–19801 (2007).

    Article  CAS  Google Scholar 

  42. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  Google Scholar 

  43. Xu, L., Xiao, N., Liu, F., Ren, H. & Gu, J. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria. Proc. Natl Acad. Sci. USA 106, 1530–1535 (2009).

    Article  CAS  Google Scholar 

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We thank H. Shu, C. R. Abraham, M. Kuro-o, R. T. Moon and Y. Yang for plasmids, H. Deng and Y. Gao for irradiation, J. Luo and T. Tong for cell lines, Z. J. Chen and M. Kuro-o for knockout mice, M. Kuro-o for comments and J. L. Teeling for revising this paper. This work was supported by grants (2010CB911801 and 2011CB503904) from the National Basic Research Program, China.

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F.L. and S.W. designed and conducted experiments, analysed the data and wrote the manuscript. H.R. carried out experiments. J.G. designed experiments and analysed the data, and wrote the manuscript.

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Correspondence to Jun Gu.

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Liu, F., Wu, S., Ren, H. et al. Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13, 254–262 (2011).

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