Inactivation of TrxR1 leads to Nrf2 activation

I’m continuing my quest on finding all possible causes of Nrf2 inhibition. Selenium is also in my focus because it’s one of the supplements that gives significant improvement to my son within a a few minutes.

After combining both subjects and going very deep into protein interactions I found a paper “TrxR1 as a potent regulator of the Nrf2-Keap1 response system” (R1)

TrxR1 is a Thioredoxin Reductase 1 - a selenoenzyme. It can be built without selenium, but when that happens it turns into cell killer (causes rapid apoptosis).

This enzyme is also a target for mercury and lead. So I decided to see what interactions it has in addition to its normal job of reducing Thioredoxins (which is also very important).

The paper proposes that TrxR1 works together with Keap1 and therefore it controls Nrf2 degradation (or activation if you will).

It seems that inactivation of TrxR1 leads to Nrf2 activation, which in turn synthesize more TrxR1 (because it’s a target gene for Nrf2).

And this was shown to happen even without oxidative stress, so inactivation of TrxR1 leads to Nrf2 activation directly.

Collectively, these observations are strongly suggestive of direct functional links between TrxR1 and Nrf2, which cannot be explained by increased oxidative stress on loss of cellular TrxR1 activity alone. … It has been suggested that a main mechanism by which most of these compounds activate Nrf2 is via covalent modification of reactive Cys residues in Keap1, as also discussed earlier.

However, based on the chemistry of known TrxR1 inhibitors and Nrf2-activating compounds, the highly reactive Sec residue in TrxR1, and the effects of TrxR1 depletion on Nrf2 activation, we here propose that TrxR1 may be a major target of most electrophilic Nrf2 activators. We also propose that inhibition of TrxR1 may be a major component of the mechanism(s) leading to Nrf2 activation. (R1)