Protein Promiscuity in H 2 O 2 Signaling.

SIGNIFICANCE: Decrypting the cellular response to oxidative stress relies on a comprehensive understanding of the redox signaling pathways stimulated under oxidizing conditions. Redox signaling events can be divided into upstream sensing of oxidants, midstream redox signaling of protein function, and downstream transcriptional redox regulation. Recent Advances: A more and more accepted theory of hydrogen peroxide (H2 O2 ) signaling is that of a thiol peroxidase redox relay, whereby protein thiols with low reactivity toward H2 O2 are instead oxidized through an oxidative relay with thiol peroxidases.

CRITICAL ISSUES: These ultrareactive thiol peroxidases are the upstream redox sensors, which form the first cellular port of call for H2 O2 . Not all redox-regulated interactions between thiol peroxidases and cellular proteins involve a transfer of oxidative equivalents, and the nature of redox signaling is further complicated through promiscuous functions of redox-regulated "moonlighting" proteins, of which the precise cellular role under oxidative stress can frequently be obscured by "polygamous" interactions. An ultimate goal of redox signaling is to initiate a rapid response, and in contrast to prokaryotic oxidant-responsive transcription factors, mammalian systems have developed redox signaling pathways, which intersect both with kinase-dependent activation of transcription factors, as well as direct oxidative regulation of transcription factors through peroxiredoxin (Prx) redox relays.

FUTURE DIRECTIONS: We highlight that both transcriptional regulation and cell fate can be modulated either through oxidative regulation of kinase pathways, or through distinct redox-dependent associations involving either Prxs or redox-responsive moonlighting proteins with functional promiscuity. These protein associations form systems of crossregulatory networks with multiple nodes of potential oxidative regulation for H2 O2 -mediated signaling. Antioxid. Redox Signal. 00, 000-000.