Alternative explanation now Nrf2 activation works

Have you heard the standard explanation how Nrf2 works?

A typical description would say that Nrf2 is released from Keap1 upon Keap1’s modification of cysteine residue, then Nrf2 translocates to nucleus and new proteins are made.

Well, I just found a paper that claims this not NOT how it works!

Instead of Nrf2 being released, it still occupies Keap1, preventing newly synthesised Nrf2 (which is produced constantly, but captured by Keap1 unless there is increased oxidative stress) from being captured.

And it was shown that the newly made Nrf2 actually returns to nucleus and initiates transcription of the target enzymes.

Nrf2 is, however, likely not released but instead occupies the now inactive Keap1, so that newly synthesized Nrf2 can translocate to the nucleus where it forms heterodimers with bZIP transcription factors such as Mafs (predominantly), c-Jun, or ATF4 before binding ARE and activating target genes.

It has been, and still is, debated whether Nrf2 also dissociates from Keap1. However, a recent study convincingly showed that Nrf2 is indeed not released from Keap1. (R1)

If this is true, it invalidates years of publications. That’s why I’m so emotional about it 🙂