高遷移率族蛋白（high mobility group box,HMGB）是一種非組蛋白染色體蛋白質(zhì)。在正常情況下位于細胞內(nèi)，參與多種生物學(xué)過程，包括維持核小體結(jié)構(gòu)、調(diào)節(jié)基因轉(zhuǎn)錄、核糖核酸形成、DNA修復(fù)、編碼免疫球蛋白可變區(qū)的V、D、J基因片段重組、分化和發(fā)展等。
Nature一項研究表明，染色體HMGB 蛋白HMGB1、 HMGB2 和HMGB3是所有由核酸受體調(diào)控的先天免疫反應(yīng)的激發(fā)所*的。HMGB蛋白與所測試的所有產(chǎn)生免疫反應(yīng)的核酸相結(jié)合（不管它們被認為是Toll樣受體的配體還是細胞溶質(zhì)配體），說明它們可能有一個生理作用，即充當(dāng)細胞內(nèi)核酸的普適性“哨兵”。
HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses
Hideyuki Yanai1,5, Tatsuma Ban1,5, ZhiChao Wang1,5, Myoung Kwon Choi1, Takeshi Kawamura2, Hideo Negishi1, Makoto Nakasato1, Yan Lu1, Sho Hangai1, Ryuji Koshiba1, David Savitsky1, Lorenza Ronfani3, Shizuo Akira4, Marco E. Bianchi3, Kenya Honda1,6, Tomohiko Tamura1, Tatsuhiko Kodama2 & Tadatsugu Taniguchi1
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.
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.
