Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases.

Apoptosis is mediated by members of the interleukin-1beta converting enzyme (ICE) family of proteases (caspases), which are activated by diverse stimuli, although the downstream molecular targets of caspases are still poorly understood. Using the modified yeast two-hybrid system, which we recently established to clone genes for caspase substrates, we identified NRF2 as a novel caspase substrate. NRF2 is a member of the NF-E2 family of basic region leucine-zipper transcription factors and has been shown to induce phase II detoxifying enzymes through anti-oxidant response elements. NRF2 was cleaved at two sites by recombinant caspase-3 in vitro as well as in HeLa cells during TNFalpha-mediated apoptosis. Overexpression of the C-terminal cleavage fragment containing the DNA binding and leucine-zipper domains induced apoptosis in HeLa cells. These observations suggest that NRF2 might have some role in the induction of apoptosis after cleavage by caspases.