HMGB proteins function as universal sentinels for nucleic acid-mediated innate immune responses

The activation of innate immune responses by nucleic acids iscrucial to protective and pathological immunities and is mediatedby the transmembrane Toll-like receptors (TLRs) and cytosolicreceptors1,2. However, it remains unknown whether a mechanismexists that integrates these nucleic-acid-sensing systems. Here weshow that high-mobility group box (HMGB) proteins 1, 2 and 3function as universal sentinels for nucleic acids.HMGBs bind to allimmunogenic nucleic acids examined with a correlation betweenaffinity and immunogenic potential. Hmgb12/2 and Hmgb22/2mouse cells are defective in type-I interferon and inflammatorycytokine induction by DNA or RNA targeted to activate the cytosolicnucleic-acid-sensing receptors; cells in which the expressionof all three HMGBs is suppressed show a more profound defect,accompanied by impaired activation of the transcription factorsinterferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kB.The absence of HMGBs also severely impairs the activation ofTLR3, TLR7 and TLR9 by their cognate nucleic acids. Our resultstherefore indicate a hierarchy in the nucleic-acid-mediated activationof immune responses, wherein the selective activation ofnucleic-acid-sensing receptors is contingent on the more promiscuoussensing of nucleic acids byHMGBs. These findings may haveimplications for understanding the evolution of the innate immunesystem and for the treatment of immunological disorders.