Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling
Yaqian Huang, Zongmin Li, Lulu Zhang, Huan Tang, Heng Zhang, Chu Wang, Selena Chen, Dingfang Bu, Zaifeng Zhang, Zhigang Zhu, Piaoliu Yuan, Kun Li, Xiao‐Qi Yu, Wei Kong, Chaoshu Tang, Young‐Eun Jung, Renan B. Ferreira, Kate S. Carroll, Junbao Du, Jing Yang, Hongfang Jin
Abstract
Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism.