ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling
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...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000345 |
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| author | Man Sup Kwak Myeonggil Han Yong Joon Lee Seoyeon Choi Jeonghwa Kim In Ho Park Jeon-Soo Shin |
| author_facet | Man Sup Kwak Myeonggil Han Yong Joon Lee Seoyeon Choi Jeonghwa Kim In Ho Park Jeon-Soo Shin |
| author_sort | Man Sup Kwak |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bf61f17c809b4fea87f91ce9d9ab8ddc |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-bf61f17c809b4fea87f91ce9d9ab8ddc2025-02-05T04:32:00ZengElsevierRedox Biology2213-23172025-03-0180103521ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signalingMan Sup Kwak0Myeonggil Han1Yong Joon Lee2Seoyeon Choi3Jeonghwa Kim4In Ho Park5Jeon-Soo Shin6Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, South Korea; Corresponding author. Department of Microbiology, Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul, 03722, South Korea.Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South KoreaDepartment of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South KoreaDepartment of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South KoreaDepartment of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South KoreaInstitute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, South Korea; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, 03722, South KoreaDepartment of Microbiology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea; Corresponding author. Department of Microbiology, Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul, 03722, South Korea.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.http://www.sciencedirect.com/science/article/pii/S2213231725000345HMGB1Reactive oxygen speciesDimerizationInflammation |
| spellingShingle | Man Sup Kwak Myeonggil Han Yong Joon Lee Seoyeon Choi Jeonghwa Kim In Ho Park Jeon-Soo Shin ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling Redox Biology HMGB1 Reactive oxygen species Dimerization Inflammation |
| title | ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling |
| title_full | ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling |
| title_fullStr | ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling |
| title_full_unstemmed | ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling |
| title_short | ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling |
| title_sort | ros anchor pamps mediated extracellular hmgb1 self association and its dimerization enhances pro inflammatory signaling |
| topic | HMGB1 Reactive oxygen species Dimerization Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000345 |
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