Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling.
Hydrogen peroxide (H(2)O(2)) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H(2)O(2) (k(app) ∼1-10 M(-1) s(-1)), can be specifically and efficiently oxidized by H(2)O(2). Moreover, cellular thiol peroxidases, which are highly abundant and efficient H(2)O(2) scavengers, should effectively eliminate virtually all of the H(2)O(2) produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H(2)O(2)-reactive proteins in the cell (k(app) ∼10(7)-10(8) M(-1) s(-1)), acts as a H(2)O(2) signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Mirko C
MC
Sobotta
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Willy
0000000190916116
W
Liou
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Sarah
S
Stöcker
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Deepti
D
Talwar
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Michael
M
Oehler
Core facility for Mass Spectrometry and Proteomics, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Thomas
T
Ruppert
Core facility for Mass Spectrometry and Proteomics, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Annette N D
AN
Scharf
Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Tobias P
000000031367973X
TP
Dick
D000975:Antioxidants / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000975:Antioxidants; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D004247:DNA; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins