title: HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses.
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. 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.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Ban
authors.forename: ZhiChao
authors.initials: Z
authors.lastname: Wang
authors.forename: Myoung Kwon
authors.initials: MK
authors.lastname: Choi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakasato
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Sho
authors.initials: S
authors.lastname: Hangai
authors.forename: Ryuji
authors.initials: R
authors.lastname: Koshiba
authors.forename: David
authors.initials: D
authors.lastname: Savitsky
authors.forename: Lorenza
authors.initials: L
authors.lastname: Ronfani
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: 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
chemical_list: 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