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HMGB1 binds to and disrupts the hairpin structure of RNA15 and inhibits toll-like receptor activation.

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Title: HMGB1 binds to and disrupts the hairpin structure of RNA15 and inhibits toll-like receptor activation.
Authors: Lin, Cong1, Li, Penghui2,3, Savitskaya, Anna G.4, Lyukmanova, Ekaterina4,5, Goncharuk, Sergey A.4, Mineev, Konstantin S.4, Du, Xiubo2, Wang, Yibo1 yibo.wang@ciac.ac.cn, Wang, Xiaohui1,6 xiaohui.wang@ciac.ac.cn
Source: Journal of Biological Chemistry. Mar2026, Vol. 302 Issue 3, p1-11. 11p.
Subjects: Toll-like receptors, High mobility group proteins, Natural immunity, RNA, Host-bacteria relationships, Inflammatory mediators, Molecular dynamics, Nucleotide sequence
Abstract: Toll-like receptor 13 (TLR13) is a critical innate immune sensor that recognizes a conserved RNA sequence, RNA15 (2054–2068, ACG GAA AGA CCC CGU), within bacterial 23S rRNA, thereby initiating a proinflammatory response. While the alarmin high mobility group box 1 (HMGB1) is known to modulate various TLR pathways, its influence on TLR13 signaling has remained unexplored. Here, we reveal that HMGB1 directly binds RNA15 with high affinity and profoundly disrupts its hairpin structure, which is essential for TLR13 recognition. Using a combination of fluorescence anisotropy, FRET assays, NMR spectroscopy, and enhancedsampling molecular dynamics simulations, we demonstrate that HMGB1 binding remodels RNA15 into a stem-open conformation, making it thermodynamically unfavorable for receptor activation. Functionally, HMGB1 significantly inhibits RNA15-induced TLR13 activation, leading to a dosedependent reduction in inflammatory mediators. These findings uncover a novel "ligand remodeling" mechanism, whereby HMGB1 acts as a negative regulator of TLR13 signaling by structurally altering the RNA ligand rather than directly blocking the receptor. This work provides new insights into host–pathogen interactions and suggests important implications for the design and immunogenicity of RNA-based therapeutics and vaccines. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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Header DbId: egs
DbLabel: Engineering Source
An: 192571822
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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  Data: HMGB1 binds to and disrupts the hairpin structure of RNA15 and inhibits toll-like receptor activation.
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  Data: <searchLink fieldCode="AR" term="%22Lin%2C+Cong%22">Lin, Cong</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Li%2C+Penghui%22">Li, Penghui</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Savitskaya%2C+Anna+G%2E%22">Savitskaya, Anna G.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Lyukmanova%2C+Ekaterina%22">Lyukmanova, Ekaterina</searchLink><relatesTo>4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Goncharuk%2C+Sergey+A%2E%22">Goncharuk, Sergey A.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Mineev%2C+Konstantin+S%2E%22">Mineev, Konstantin S.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Du%2C+Xiubo%22">Du, Xiubo</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Wang%2C+Yibo%22">Wang, Yibo</searchLink><relatesTo>1</relatesTo><i> yibo.wang@ciac.ac.cn</i><br /><searchLink fieldCode="AR" term="%22Wang%2C+Xiaohui%22">Wang, Xiaohui</searchLink><relatesTo>1,6</relatesTo><i> xiaohui.wang@ciac.ac.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Mar2026, Vol. 302 Issue 3, p1-11. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Toll-like+receptors%22">Toll-like receptors</searchLink><br /><searchLink fieldCode="DE" term="%22High+mobility+group+proteins%22">High mobility group proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Natural+immunity%22">Natural immunity</searchLink><br /><searchLink fieldCode="DE" term="%22RNA%22">RNA</searchLink><br /><searchLink fieldCode="DE" term="%22Host-bacteria+relationships%22">Host-bacteria relationships</searchLink><br /><searchLink fieldCode="DE" term="%22Inflammatory+mediators%22">Inflammatory mediators</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleotide+sequence%22">Nucleotide sequence</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Toll-like receptor 13 (TLR13) is a critical innate immune sensor that recognizes a conserved RNA sequence, RNA15 (2054–2068, ACG GAA AGA CCC CGU), within bacterial 23S rRNA, thereby initiating a proinflammatory response. While the alarmin high mobility group box 1 (HMGB1) is known to modulate various TLR pathways, its influence on TLR13 signaling has remained unexplored. Here, we reveal that HMGB1 directly binds RNA15 with high affinity and profoundly disrupts its hairpin structure, which is essential for TLR13 recognition. Using a combination of fluorescence anisotropy, FRET assays, NMR spectroscopy, and enhancedsampling molecular dynamics simulations, we demonstrate that HMGB1 binding remodels RNA15 into a stem-open conformation, making it thermodynamically unfavorable for receptor activation. Functionally, HMGB1 significantly inhibits RNA15-induced TLR13 activation, leading to a dosedependent reduction in inflammatory mediators. These findings uncover a novel "ligand remodeling" mechanism, whereby HMGB1 acts as a negative regulator of TLR13 signaling by structurally altering the RNA ligand rather than directly blocking the receptor. This work provides new insights into host–pathogen interactions and suggests important implications for the design and immunogenicity of RNA-based therapeutics and vaccines. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2026.111155
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 11
        StartPage: 1
    Subjects:
      – SubjectFull: Toll-like receptors
        Type: general
      – SubjectFull: High mobility group proteins
        Type: general
      – SubjectFull: Natural immunity
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      – SubjectFull: RNA
        Type: general
      – SubjectFull: Host-bacteria relationships
        Type: general
      – SubjectFull: Inflammatory mediators
        Type: general
      – SubjectFull: Molecular dynamics
        Type: general
      – SubjectFull: Nucleotide sequence
        Type: general
    Titles:
      – TitleFull: HMGB1 binds to and disrupts the hairpin structure of RNA15 and inhibits toll-like receptor activation.
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            NameFull: Lin, Cong
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            NameFull: Li, Penghui
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            NameFull: Lyukmanova, Ekaterina
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            – D: 01
              M: 03
              Text: Mar2026
              Type: published
              Y: 2026
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