Absence of Cytosolic 2-Cys Prx Subtypes I and II Exacerbates TNF-α-Induced Apoptosis via Different Routes
Sunmi Lee,
Joo Young Lee,
Eun Woo Lee,
Sujin Park,
Dong Hoon Kang,
Chengchun Min,
Doo Jae Lee,
Dongmin Kang,
Jaewhan Song,
Jongbum Kwon,
Sang Won Kang
Affiliations
Sunmi Lee
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea
Joo Young Lee
Department of Life Science, Ewha Womans University, Seoul 03760, Korea
Eun Woo Lee
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
Sujin Park
Department of Life Science, Ewha Womans University, Seoul 03760, Korea
Dong Hoon Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea
Chengchun Min
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea
Doo Jae Lee
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea
Dongmin Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Korea
Jaewhan Song
Department of Biochemistry, Yonsei University, Seoul 03722, Korea
Jongbum Kwon
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea
Sang Won Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea; Corresponding author
Summary: There are abundant peroxiredoxin (Prx) enzymes, but an increase of cellular H2O2 level always happens in apoptotic cells. Here, we show that cellular H2O2 switches different apoptosis pathways depending on which type of Prx enzyme is absent. TNF-α-induced H2O2 burst preferentially activates the DNA damage-dependent apoptosis pathway in the absence of PrxI. By contrast, the same H2O2 burst stimulates the RIPK1-dependent apoptosis pathway in the absence of PrxII by inducing the destruction of cIAP1 in caveolar membrane. Specifically, H2O2 induces the oxidation of Cys308 residue in the cIAP1-BIR3 domain, which induces the dimerization-dependent E3 ligase activation. Thus, the reduction in cIAP level by the absence of PrxII triggers cell-autonomous apoptosis in cancer cells and tumors. Such differential functions of PrxI and PrxII are mediated by interaction with H2AX and cIAP1, respectively. Collectively, this study reveals the distinct switch roles of 2-Cys Prx isoforms in apoptosis signaling. : Lee et al. show that the 2-Cys peroxiredoxin (Prx) isoforms, Prx I and Prx II, discretely regulate different apoptosis pathways. Specifically, the absence of Prx I augments apoptosis through the DNA damage response, while the absence of Prx II switches RIPK1-dependent apoptosis by causing cIAP1 depletion. Keywords: peroxiredoxin, apoptosis, H2O2, TNF-α, cIAP, DNA damage, RIPK1