Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) plays essential roles in cellular signaling.  The best-described role for NO is activation of soluble guanylate cyclase leading to the production of cyclic GMP (cGMP).  However, evidence continues to point toward cGMP-independent NO signaling pathways involving S-nitrosation of cysteine residues.  Once formed, S-nitrosothiols are transferred in vivo through protein-protein interaction driven transnitrosation reactions.  Here, we provide evidence through detailed kinetic analyses that transnitrosation signaling pathways can be initiated through auto-S-nitrosation of the NOS Zn2+-tetrathiolate.  Downstream, S-nitrosated NOS can form S-nitrosoglutathione (GSNO).  GSNO then transnitrosates thioredoxin, which then transnitrosates Caspase-3 resulting in loss of caspase activity and inhibition of apoptosis.  In a separate pathway, S-nitrosated NOS may transnitrosate GAPDH resulting in translocation of GAPDH to the nucleus.  GAPDH can then transnitrosate the nuclear sirtuins, Sirt1 and Sirt6, resulting in inhibition of sirtuin deacetylase activity and control of gene silencing.

Transnitrosation signaling pathways initiated by <i>S</i>-nitrosation of the nitric oxide synthase Zn<sup>2+</sup>-tetrathiolate

243rd National Meeting (2012)

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Transnitrosation signaling pathways initiated by S-nitrosation of the nitric oxide synthase Zn2+-tetrathiolate

Transnitrosation signaling pathways initiated by S-nitrosation of the nitric oxide synthase Zn²⁺-tetrathiolate