Soluble guanylyl cyclase mediates noncanonical nitric oxide signaling by nitrosothiol transfer under oxidative stress
Chuanlong Cui, Changgong Wu, Ping Shu, Tong Liu, Hong Li, Annie Beuve
Abstract
Soluble guanylyl cyclase (GC1) is an α/β heterodimer producing cGMP when stimulated by nitric oxide (NO). The NO-GC1-cGMP pathway is essential for cardiovascular homeostasis but is disrupted by oxidative stress, which causes GC1 desensitization to NO by heme oxidation and S-nitrosation (SNO) of specific cysteines. We discovered that under these conditions, GC1-α subunit increases cellular S-nitrosation via transfer of nitrosothiols to other proteins (transnitrosation) in cardiac and smooth muscle cells. One of the GC1 SNO-targets was the oxidized form of Thioredoxin1 (oTrx1), which is unidirectionally transnitrosated by GC1 with αC610 as a SNO-donor. Because oTrx1 itself drives transnitrosation, we sought and identified SNO-proteins targeted by both GC1 and Trx1. We found that transnitrosation of the small GTPase RhoA by SNO-GC1 requires oTrx1 as a nitrosothiol relay, suggesting a SNO-GC1→oTrx1→RhoA cascade. The RhoA signaling pathway, which is antagonized by the canonical NO-cGMP pathway, was alternatively inhibited by GC1-α-dependent S-nitrosation under oxidative conditions. We propose that SNO-GC1, via transnitrosation, mediates adaptive responses triggered by oxidation of the canonical NO-cGMP pathway.