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

@article{citeulike:6095849, 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)-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.}, author = {Yanai, Hideyuki and Ban, Tatsuma and Wang, ZhiChao and Choi, Myoung K. and Kawamura, Takeshi and Negishi, Hideo and Nakasato, Makoto and Lu, Yan and Hangai, Sho and Koshiba, Ryuji and Savitsky, David and Ronfani, Lorenza and Akira, Shizuo and Bianchi, Marco E. and Honda, Kenya and Tamura, Tomohiko and Kodama, Tatsuhiko and Taniguchi, Tadatsugu}, citeulike-article-id = {6095849}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nature08512}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature08512}, day = {05}, doi = {10.1038/nature08512}, issn = {0028-0836}, journal = {Nature}, keywords = {hmgb1, innate\_immunity, tlr}, month = {November}, number = {7269}, pages = {99--103}, posted-at = {2009-11-10 21:50:17}, priority = {0}, publisher = {Nature Publishing Group}, title = {HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses }, url = {http://dx.doi.org/10.1038/nature08512}, volume = {462}, year = {2009} }

TY - JOUR ID - citeulike:6095849 L3 - citeulike-article-id:6095849 N2 - 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)-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. IS - 7269 JF - Nature SN - 0028-0836 EP - 103 TI - HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses PB - Nature Publishing Group VL - 462 SP - 99 KW - hmgb1 KW - innate_immunity KW - tlr AU - Yanai, Hideyuki AU - Ban, Tatsuma AU - Wang, ZhiChao AU - Choi, Myoung AU - Kawamura, Takeshi AU - Negishi, Hideo AU - Nakasato, Makoto AU - Lu, Yan AU - Hangai, Sho AU - Koshiba, Ryuji AU - Savitsky, David AU - Ronfani, Lorenza AU - Akira, Shizuo AU - Bianchi, Marco AU - Honda, Kenya AU - Tamura, Tomohiko AU - Kodama, Tatsuhiko AU - Taniguchi, Tadatsugu PY - 2009/11/05/ UR - http://dx.doi.org/10.1038/nature08512 ER -