S-nitrosylation of proteins by nitric oxide (NO) is a major mode of signaling in cells, playing major roles in both health and disease (Foster et al., 2009). S-nitrosylation mediates the regulation of a range of proteins, including prominent nuclear proteins such as such as HDAC2 (Nott et al., 2008) and PARP1 (Yu et al., 2006). The high reactivity of the NO group with protein thiols, but the selective nature of nitrosylation within the cell, implies the existence of targeting mechanisms. Specificity of NO signaling can be achieved by the binding of NO synthase (NOS) to target proteins, either directly (Kim et al., 2005) or through scaffolding proteins such as PSD-95 (Lipton et al., 2002) and CAPON (Fang et al., 2000). Of the vast number of nitrosylated proteins, however, only a small subset have been shown to bind to NOS, and NOS does not reside within all cellular compartments. The three principal isoforms of NOS - neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) - are primarily non-nuclear, and thus the mechanisms by which nuclear proteins are selectively nitrosylated remain unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is physiologically nitrosylated at its Cys150 residue, which leads to its translocation into the nucleus (Nara et al., 2005). We now show that nitrosylated GAPDH (SNO-GAPDH) acts as a nuclear nitrosylase, physiologically transnitrosylating the nuclear proteins sirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2), and DNA-activated protein kinase (DNA-PK). Our findings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest that protein-protein transfer of NO groups may be a general mechanism in cellular signal transduction.
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