Abstract
The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors1,2. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1-/- and Hmgb2-/- mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders.
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Acknowledgements
We thank C. Reis e Sousa and J. Rehwinkel for 5′-triphosphate RNA;, Y. Kawaguchi for HSV-1 DNA; A. Katoh and M. Kidokoro for the vaccinia virus (MO) genome for ligand stimulation; J. Vilcek, R. Medzhitov, R. Schekman, J. V. Ravetch and H. Ohno for invaluable advice; and R. Takeda, M. Shishido, Y. Nakaima and T. Oh for technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas ‘Integrative Research Toward the Conquest of Cancer,’ Grant-in-Aid for Scientific Research (A), and Global Center of Excellence Program ‘Integrative Life Science Based on the Study of Biosignaling Mechanisms’ from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by the Korea Science and Engineering Foundation Grant. T.B. and Z.W. are research fellows of the Japan Society for the Promotion of Science.
Author Contributions H.Y., T.B., Z.W. and M.C. designed, performed and analysed most of the experiments in this study. T. Kawamura and T. Kodama collected data and performed the mass spectrometry analysis. H.N. performed experiments on RAW264.7 cells. M.N. performed the fluorescence microscopy analysis. Y.L. and R.K. cloned the constructs. S.H. assisted with the virus infection experiments. A.S., L.R. and M.B. provided precious materials and invaluable advice. K.H., T. Tamura and T. Taniguchi provided overall coordination with respect to conception, design and supervision of the study. H.Y., T.B., D.S., T. Tamura and T. Taniguchi wrote the manuscript with comments from the co-authors.
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Yanai, H., Ban, T., Wang, Z. et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses . Nature 462, 99–103 (2009). https://doi.org/10.1038/nature08512
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DOI: https://doi.org/10.1038/nature08512
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