Bräutigam, L., Jensen, L.D., Poschmann, G., Nyström, S., Bannenberg, S., Dreij, K., Lepka, K., Prozorovski, T., Montano, S.J., Aktas, O., Uhlén, P., Stühler, K., Cao, Y., Holmgren, A., and Berndt, C. (2013) Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1. Proc. Natl. Acad. Sci. USA. 110(50):20057-20062.
Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation
cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational
modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified
for glutaredoxin 2, a vertebrate-specific glutathione–disulfide oxidoreductase with a critical role for embryonic brain development.
Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse
studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism
to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation
of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD+-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic
region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation
controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results
link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.