Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons

Significance S -nitrosylation, addition of an NO group to a cysteine thiol, can regulate protein activity. Aberrant proteinS -nitrosylation, however, can disrupt normal enzyme function, as is the case forS -nitrosylated peroxiredoxin (SNO-Prx), which would otherwise catabolize toxic peroxides that occur under neurodegenerative conditions such as Parkinson’s disease. Here, we describe a paradigm ofN -phosphorylation–mediated denitrosylation by the enzyme sulfiredoxin that removes NO from Prx. The findings are at the center of redox control of the cell, explaining reactivation by sulfiredoxin of both Prx-SO2 H and SNO-Prx and thus describe a master regulator of redox reactions that combats nitrosative and oxidative stress in cells. These results suggest that sulfiredoxin may be an important target for therapeutic intervention in neurodegenerative disorders.