Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli
Man Sup Kwak,
Hee Sue Kim,
Khulan Lkhamsuren,
Young Hun Kim,
Myeong Gil Han,
Jae Min Shin,
In Ho Park,
Woo Joong Rhee,
Se Kyoung Lee,
Sue Goo Rhee,
Jeon-Soo Shin
Affiliations
Man Sup Kwak
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Hee Sue Kim
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Khulan Lkhamsuren
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Young Hun Kim
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Myeong Gil Han
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Jae Min Shin
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
In Ho Park
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea
Woo Joong Rhee
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea
Se Kyoung Lee
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea
Sue Goo Rhee
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea
Jeon-Soo Shin
Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, South Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, South Korea; Corresponding author. Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, South Korea.
The nuclear protein HMGB1 (high mobility group box 1) is secreted by monocytes-macrophages in response to inflammatory stimuli and serves as a danger-associated molecular pattern. Acetylation and phosphorylation of HMGB1 are implicated in the regulation of its nucleocytoplasmic translocation for secretion, although inflammatory stimuli are known to induce H2O2 production. Here we show that H2O2-induced oxidation of HMGB1, which results in the formation of an intramolecular disulfide bond between Cys23 and Cys45, is necessary and sufficient for its nucleocytoplasmic translocation and secretion. The oxidation is catalyzed by peroxiredoxin I (PrxI) and PrxII, which are first oxidized by H2O2 and then transfer their disulfide oxidation state to HMGB1. The disulfide form of HMGB1 showed higher affinity for nuclear exportin CRM1 compared with the reduced form. Lipopolysaccharide (LPS)–induced HMGB1 secretion was greatly attenuated in macrophages derived from PrxI or PrxII knockout mice, as was the LPS-induced increase in serum HMGB1 levels. Keywords: HMGB1, Oxidation, Secretion, Peroxiredoxin, H2O2
