Characterization of mammalian glutaredoxin isoforms as S-denitrosylases

Glutaredoxins (Grx) are involved in many reactions including defense against oxidative stress. However, the role of the Grx system under nitrosative stress has barely been investigated. In this study, we found that human Grxs denitrosylated both low and high molecular weight S-nitrosothiols. Some S-nitrosylated proteins, stable in the presence of a physiological concentration of glutathione (GSH), were denitrosylated by Grxs. Caspase 3 and cathepsin B were identified as substrates of Grx1-catalysed denitrosylation. In addition, mono-thiol Grxs, such as Grx5, exhibited denitrosylase activity coupled with GSH via a monothiol mechanism. Our study demonstrates the ability of Grxs to act as S-denitrosylases and pinpoint a new mechanism for denitrosylation.