HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses.
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. 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)-kappaB. 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.
Yanai
Hideyuki
H
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Ban
Tatsuma
T
Wang
ZhiChao
Z
Choi
Myoung Kwon
MK
Kawamura
Takeshi
T
Negishi
Hideo
H
Nakasato
Makoto
M
Lu
Yan
Y
Hangai
Sho
S
Koshiba
Ryuji
R
Savitsky
David
D
Ronfani
Lorenza
L
Akira
Shizuo
S
Bianchi
Marco E
ME
Honda
Kenya
K
Tamura
Tomohiko
T
Kodama
Tatsuhiko
T
Taniguchi
Tadatsugu
T
D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000276:immunology; D004247:DNA / Q000276:immunology; D024002:HMGB Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D024243:HMGB1 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D024261:HMGB2 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism; D009696:Nucleic Acids / Q000276:immunology*; D009711:Nucleotides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D012313:RNA / Q000276:immunology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology / Q000821:virology
D024002:HMGB Proteins; D024243:HMGB1 Protein; D024261:HMGB2 Protein; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D016328:NF-kappa B; D009696:Nucleic Acids; D009711:Nucleotides; D051193:Toll-Like Receptors; D012313:RNA; D004247:DNA