Absence of Cytosolic 2-Cys Prx Subtypes I and II Exacerbates TNF-α-Induced Apoptosis via Different Routes

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. [Display omitted] •Absence of Prx I and Prx II exacerbates TNF-α-induced apoptosis in cancer cells.•Prx I binds histone H2AX and inhibits DNA damage-dependent apoptosis.•Prx II binds and prevents the oxidative activation of cIAP1 E3 ligase.•Absence of Prx II induces cell-autonomous apoptosis and inhibits tumor growth. 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.