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조회187

연세대학교 의과대학

Redox Biol., Jan 31 2025, 80 S2213-2317(25)00034-5 | https://doi.org/10.1016/j.redox.2025.103521 ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling

Man Sup Kwak ^a,b, Myeonggil Han^a,c, Yong Joon Lee^a, Seoyeon Choi ^a,c, Jeonghwa Kim^a,c, In Ho Park ^b,d, Jeon-Soo Shin ^a,b,c

^aDepartment of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea
^bInstitute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, South Korea
^cBrain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea
^dDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul, 03722, South Korea

Corresponding authors: Man Sup Kwak, Jeon-Soo Shin

Abstract

Many cellular proteins form homo- or hetero-oligomeric complexes through dimerization, and ligand oligomerization is crucial for inducing receptor oligomerization. Intermolecular disulfide bond formation is critical for protein oligomerization that regulates biological functions. HMGB1 is a nuclear protein that acts as a DAMP when secreted. HMGB1 is redox-sensitive, contains three cysteines: Cys²³, Cys⁴⁵, and Cys¹⁰⁶, and its function varies depending on the redox state of the extracellular space. However, the homo-dimerization of extracellular HMGB1 and its immunological significance have not been identified. In this study, we investigated the immunological significance of Cys¹⁰⁶-mediated HMGB1 homo-dimerization. In the extracellular environment, LPS and LTA induced HMGB1 self-association leading to H₂O₂ anchoring Cys¹⁰⁶-Cys¹⁰⁶-mediated HMGB1 intermolecular disulfide bond formation. Despite treatment with H₂O₂, LPS, or LTA, HMGB1 dimerization was blocked in presence of Cys¹⁰⁶ residue mutation, the ROS scavenger NAC, and the thiol-reducing agent DTT. Inflammatory stimulation induced the secretion of monomeric HMGB1 but not dimeric HMGB1. HMGB1 dimerization was promoted by PAMPs and H₂O₂ in the extracellular environment. Compared to monomeric HMGB1, Cys¹⁰⁶-Cys¹⁰⁶-linked dimeric HMGB1 significantly enhanced intracellular NF-κB signaling and cytokine production through increased direct binding affinity for TLR2 and TLR4 and effective HMGB1-mediated delivery of PAMPs to their receptors. Therefore, we have demonstrated that dimeric HMGB1 enhances its effect on pro-inflammatory signaling.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-02-12)
연구진국내 연구진
분야 의약학 > 면역의학

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