1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
2. Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan
3. Faculty of Medicine, San Raffaele University, via Olgettina 58, 20132 Milan, Italy
4. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan
5. These authors contributed equally to this work.
6. Present address: Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita, Osaka 565-0871, Japan.

Correspondence to: Tadatsugu Taniguchi¹ Correspondence and requests for materials should be addressed to T. Taniguchi (Email: tada@m.u-tokyo.ac.jp).

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 receptors^{1, 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)-B. 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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