Peroxiredoxins constitute a major family of cysteine-based peroxide-scavenging enzymes. They carry an intriguing redox switch by undergoing substrate-mediated inactivation via overoxidation of their catalytic cysteine to the sulfinic acid form that is reverted by reduction catalyzed by the sulfinic acid reductase sulfiredoxin (Srx). The biological significance of such inactivation is not understood, nor is the function of Srx1. To address this question, we generated a mouse line with a null deletion of the Srx1-encoding Srxn1 gene. We show here that Srxn1−/− mice are perfectly viable and do not suffer from any apparent defects under laboratory conditions, but have an abnormal response to lipopolysaccharide that manifests by increased mortality during endotoxic shock. Microarray-based mRNA profiles show that although the response of Srxn1−/− mice to lipopolysaccharide is typical, spanning all spectrum and all pathways of innate immunity, it is delayed by several hours and remains intense when the response of Srxn1+/+ mice has already dissipated. These data indicate that Srx1 activity protects mice from the lethality of endotoxic shock, adding this enzyme to other host factors, as NRF2 and peroxiredoxin 2, which by regulating cellular reactive oxygen species levels act as important modifiers in the pathogenesis of sepsis. Antioxid. Redox Signal. 14, 2071–2080.
Get full access to this article
View all access options for this article.
References
1.
BabiorBM. Phagocytes and oxidative stress. Am J Med, 109:33–44. 2000.
2.
BaeSH, WooHA, SungSH, LeeHE, LeeSK, KilIS, RheeSG. Induction of sulfiredoxin via an Nrf2-dependent pathway and hyperoxidation of peroxiredoxin III in the lungs of mice exposed to hyperoxia. Antioxid Redox Signal, 11:937–948. 2009.
3.
BeutlerB. Inferences, questions and possibilities in Toll-like receptor signalling. Nature, 430:257–263. 2004.
4.
BiteauB, LabarreJ, ToledanoMB. ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin. Nature, 425:980–984. 2003.
5.
BogdanC, RollinghoffM, DiefenbachA. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol, 12:64–76. 2000.
6.
BozonetSM, FindlayVJ, DayAM, CameronJ, VealEA, MorganBA. Oxidation of a eukaryotic 2-Cys peroxiredoxin is a molecular switch controlling the transcriptional response to increasing levels of hydrogen peroxide. J Biol Chem, 280:23319–23327. 2005.
BuchouT, VernetM, BlondO, JensenHH, PointuH, OlsenBB, CochetC, IssingerOG, BoldyreffB. Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol, 23:908–915. 2003.
9.
BudanovAV, SablinaAA, FeinsteinE, KooninEV, ChumakovPM. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science, 304:596–600. 2004.
10.
ChangTS, JeongW, WooHA, LeeSM, ParkS, RheeSG. Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine. J Biol Chem, 279:50994–51001. 2004.
11.
ChevalletM, WagnerE, LucheS, van DorsselaerA, Leize-WagnerE, RabilloudT. Regeneration of peroxiredoxins during recovery after oxidative stress: only some overoxidized peroxiredoxins can be reduced during recovery after oxidative stress. J Biol Chem, 278:37146–37153. 2003.
12.
CohenJ. The immunopathogenesis of sepsis. Nature, 420:885–891. 2002.
13.
DietA, AbbasK, BoutonC, GuillonB, TomaselloF, FourquetS, ToledanoMB, DrapierJC. Regulation of peroxiredoxins by nitric oxide in immunostimulated macrophages. J Biol Chem, 282:36199–36205. 2007.
14.
DinarelloCA. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest, 112:321S–329S. 1997.
15.
Dinkova-KostovaAT, HoltzclawWD, KenslerTW. The role of Keap1 in cellular protective responses. Chem Res Toxicol, 18:1779–1791. 2005.
16.
EglerRA, FernandesE, RothermundK, SereikaS, de Souza-PintoN, JarugaP, DizdarogluM, ProchownikEV. Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1. Oncogene, 24:8038–8050. 2005.
17.
EisenMB, SpellmanPT, BrownPO, BotsteinD. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A, 95:14863–14868. 1998.
18.
FourquetS, HuangME, D'AutreauxB, ToledanoMB. The dual functions of thiol-based peroxidases in H2O2 scavenging and signaling. Antioxid Redox Signal, 10:1565–1576. 2008.
19.
GlauserDA, BrunT, GauthierBR, SchlegelW. Transcriptional response of pancreatic beta cells to metabolic stimulation: large scale identification of immediate-early and secondary response genes. BMC Mol Biol, 8:54. 2007.
20.
HayesJD, McMahonM. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci, 34:176–188. 2009.
21.
HuangME, KolodnerRD. A biological network in Saccharomyces cerevisiae prevents the deleterious effects of endogenous oxidative DNA damage. Mol Cell, 17:709–720. 2005.
22.
KollsJK. Oxidative stress in sepsis: a redox redux. J Clin Invest, 116:860–863. 2006.
23.
KongX, ThimmulappaR, KombairajuP, BiswalS. NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice. J Immunol, 185:569–577. 2010.
24.
LeY, ZhouY, IribarrenP, WangJ. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell Mol Immunol, 1:95–104. 2004.
25.
LiL, ShojiW, TakanoH, NishimuraN, AokiY, TakahashiR, GotoS, KaifuT, TakaiT, ObinataM. Increased susceptibility of MER5 (peroxiredoxin III) knockout mice to LPS-induced oxidative stress. Biochem Biophys Res Commun, 355:715–721. 2007.
NeumannCA, KrauseDS, CarmanCV, DasS, DubeyDP, AbrahamJL, BronsonRT, FujiwaraY, OrkinSH, Van EttenRA. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature, 424:561–565. 2003.
29.
NiethammerP, GrabherC, LookAT, MitchisonTJ. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature, 459:996–999. 2009.
RaguS, FayeG, IraquiI, Masurel-HenemanA, KolodnerRD, HuangME. Oxygen metabolism and reactive oxygen species cause chromosomal rearrangements and cell death. Proc Natl Acad Sci U S A, 104:9747–9752. 2007.
32.
RheeSG, ChaeHZ, KimK. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med, 38:1543–1552. 2005.
ThimmulappaRK, LeeH, RangasamyT, ReddySP, YamamotoM, KenslerTW, BiswalS. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest, 116:984–995. 2006.
35.
ToledanoMB, PlansonAG, Delaunay-MoisanA. Reining in H(2)O(2) for safe signaling. Cell, 140:454–456. 2010.
36.
VictorVM, RochaM, De la FuenteM. Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol, 4:327–347. 2004.
37.
VivancosAP, CastilloEA, BiteauB, NicotC, AyteJ, ToledanoMB, HidalgoE. A cysteine-sulfinic acid in peroxiredoxin regulates H2O2-sensing by the antioxidant Pap1 pathway. Proc Natl Acad Sci U S A, 102:8875–8880. 2005.
38.
WooHA, BaeSH, ParkS, RheeSG. Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid Redox Signal, 11:739–745. 2009.
39.
WooHA, JeongW, ChangTS, ParkKJ, ParkSJ, YangJS, RheeSG. Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins. J Biol Chem, 280:3125–3128. 2005.
40.
WooHA, KangSW, KimHK, YangKS, ChaeHZ, RheeSG. Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteine-containing sequence. J Biol Chem, 278:47361–47364. 2003.
41.
WooHA, YimSH, ShinDH, KangD, YuDY, RheeSG. Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell, 140:517–528. 2010.
42.
WoodZA, PooleLB, KarplusPA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science, 300:650–653. 2003.
43.
WoodZA, SchroderE, Robin HarrisJ, PooleLB. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci, 28:32–40. 2003.
44.
YangCS, LeeDS, SongCH, AnSJ, LiS, KimJM, KimCS, YooDG, JeonBH, YangHY, LeeTH, LeeZW, El-BennaJ, YuDY, JoEK. Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock. J Exp Med, 204:583–594. 2007.
45.
ZmijewskiJW, LorneE, ZhaoX, TsurutaY, ShaY, LiuG, AbrahamE. Antiinflammatory effects of hydrogen peroxide in neutrophil activation and acute lung injury. Am J Respir Crit Care Med, 179:694–704. 2009.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
