HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses
HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses
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DOI：
10.1038/nature08512
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发表时间：
2009-11-05
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
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作者：
Yanai, Hideyuki;Ban, Tatsuma;Taniguchi, Tadatsugu
核酸激活先天免疫应答对保护性和病理性免疫至关重要，并由跨膜Toll样受体（TLR）和胞质受体介导（1，2）。然而，它仍然是未知的，是否存在一种机制，整合这些核酸传感系统。在这里，我们表明，高迁移率族蛋白（HMGB）蛋白1，2和3的功能作为通用的哨兵核酸。HMGBs结合所有免疫原性核酸，检查亲和力和免疫原性潜力之间的相关性。Hmgb 1（-/-）和Hmgb 2（-/-）小鼠细胞在通过靶向激活胞质核酸感应受体的DNA或RNA诱导I型干扰素和炎性细胞因子方面存在缺陷;所有三种HMGBs表达均受到抑制的细胞显示出更严重的缺陷，伴有转录因子干扰素调节因子3（IRF 3）和核因子（NF）-κ B的激活受损。HMGB的缺乏也严重损害了TLR 3、TLR 7和TLR 9通过其同源核酸的活化。因此，我们的研究结果表明，在核酸介导的免疫反应的激活，其中的选择性激活的核酸传感受体是偶然的HMGBs的核酸更混杂的传感层次。这些发现可能对理解先天免疫系统的进化和免疫疾病的治疗有影响。
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(1,2). 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)-kappa 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.