There are abundant peroxiredoxin (Prx) enzymes, but an increase of cellular H 2 O 2 level always happens in apoptotic cells. Here, we show that cellular H 2 O 2 switches different apoptosis pathways depending on which type of Prx enzyme is absent. TNF-α-induced H 2 O 2 burst preferentially activates the DNA damage-dependent apoptosis pathway in the absence of PrxI. By contrast, the same H 2 O 2 burst stimulates the RIPK1-dependent apoptosis pathway in the absence of PrxII by inducing the destruction of cIAP1 in caveolar membrane. Specifically, H 2 O 2 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.
Bibliographical noteFunding Information:
We thank Dr. Michael Karin for providing IKK-deficient 3T3 cell lines, Dr. Sue Goo Rhee for encouragement, and the lab members for technical assistance. This study was supported by grants from the National Research Foundation of Korea ( 2018R1A2B3006323 , 2017M3A9B6073098 , and 2012R1A5A1048236 ).
© 2019 The Author(s)
- DNA damage
- H O