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

Abstract

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.

Keywords: DNA damage; H(2)O(2); RIPK1; TNF-α; apoptosis; cIAP; peroxiredoxin.