Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli

Abstract

The nuclear proteinHMGB1(high mobility group box 1) is secreted by monocytes-macrophages inresponsetoinflammatorystimuliand serves as a danger-associated molecular pattern. Acetylation and phosphorylation ofHMGB1are implicated in the regulation of itsnucleocytoplasmictranslocationforsecretion, althoughinflammatorystimuliare known to induce H2O2production. Here we show that H2O2-induced oxidation ofHMGB1, which results in theformationof an intramoleculardisulfidebondbetween Cys23and Cys45, is necessary and sufficient for itsnucleocytoplasmictranslocationandsecretion. The oxidation is catalyzed by peroxiredoxin I (PrxI) and PrxII, which are first oxidized by H2O2and then transfer theirdisulfideoxidation state toHMGB1. Thedisulfideform ofHMGB1showed higher affinity for nuclear exportin CRM1 compared with the reduced form. Lipopolysaccharide (LPS)-inducedHMGB1secretionwas greatly attenuated in macrophages derived from PrxI or PrxII knockout mice, as was the LPS-induced increase in serumHMGB1levels.