Induction of sulfiredoxin via an Nrf2-dependent pathway and hyperoxidation of peroxiredoxin III in the lungs of mice exposed to hyperoxia.
The cysteine residue at the active site of peroxiredoxin (Prx) I, Prx II, or Prx III is reversibly hyperoxidized to cysteine sulfinic acid, with concomitant loss of peroxidase activity, during normal catalysis. Sulfiredoxin (Srx) is the enzyme responsible for reversing this hyperoxidation. We now show that the expression of Srx at both the mRNA and protein levels is increased markedly in the lungs of mice exposed to hyperoxia. This hyperoxia-induced expression of Srx was not evident in mice deficient in the transcription factor Nrf2, indicating an essential role for an Nrf2 signaling pathway in this effect. Hyperoxia also elicited the accumulation of the sulfinic form of the mitochondrial enzyme Prx III, but not that of the cytosolic enzymes Prx I or Prx II, in lung tissue. This selective hyperoxidation of Prx III is likely due either to mitochondria being the major site of the hyperoxia-induced production of reactive oxygen species or to the translocation of Srx from the cytosol into mitochondria being rate limiting for the reduction of sulfinic Prx III. Hyperoxia induced the degradation of Prx III in Nrf2-deficient mice but not in wild-type animals, suggesting that, in the absence of a sufficient amount of Srx, sulfinic Prx III is converted to a form that is susceptible to proteolysis.
Bae
Soo Han
SH
Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
Woo
Hyun Ae
HA
Sung
Su Haeng
SH
Lee
Hye Eun
HE
Lee
Se Kyoung
SK
Kil
In Sup
IS
Rhee
Sue Goo
SG
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000096:biosynthesis* / Q000235:genetics; D054464:Peroxiredoxins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D054464:Peroxiredoxins; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse