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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.

journal_name

Nature

journal_title

Nature

authors

Yanai H,Ban T,Wang Z,Choi MK,Kawamura T,Negishi H,Nakasato M,Lu Y,Hangai S,Koshiba R,Savitsky D,Ronfani L,Akira S,Bianchi ME,Honda K,Tamura T,Kodama T,Taniguchi T

doi

10.1038/nature08512

subject

Has Abstract

pub_date

2009-11-05 00:00:00

pages

99-103

issue

7269

eissn

0028-0836

issn

1476-4687

pii

nature08512

journal_volume

462

pub_type

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