The protein Nrf2 plays a crucial role in tissue repair and in the protection against carcinogenesis. Cell biologists from ETH Zurich have now discovered a previously unknown role for this molecular switch, which activates numerous genes that protect cells from stress: it prevents cell damage in the skin caused by UVB rays from the sunlight. In addition, they unraveled the underlying mechanisms of action.
UVB rays are dangerous because they can cause skin cancer. On the one hand, they damage the genetic substance, DNA, directly; on the other hand, they induce the formation of highly reactive molecules in the cell, the oxygen radicals, which in turn damage the cell membrane or can attack and damage the strands of DNA. If the cell fails to repair the genetic material in time, it accumulates damaged DNA, and this frequently results in the development of skin cancer.
However, the skin is not defenseless against UVB radiation: cells in the epidermis, so-called keratinocytes, have remarkable strategies to repair or even prevent damage to the DNA, proteins and membranes.
There is a gradient of the protein Nrf2 in the epidermis that protects the outermost cells from UVB radiation; the cells underneath, however, contain low amounts of Nrf2 and die off more quickly.
Image credit: Diagram: M. Schäfer / ETH Zurich
Key factor against UVB damage
This is where Nrf2 comes in. The protein has long been recognized as an important factor in the wound healing process and plays a key protective role in many stress situations; however, researchers around Sabine Werner, a professor of cell biology at ETH Zurich, have now identified Nrf2 as a key factor in the skin’s response to UVB radiation.
The protein switch Nrf2 is a so-called transcription factor; these proteins activate specific genes the cell needs in a particular situation. If the skin is now exposed to UVB, it is protected by a series of mechanisms triggered by Nrf2. The protective molecule glutathione (GSH), which consists of three amino acids, plays a central role here, capturing the aggressive radicals and rendering them harmless. This protective mechanism also extends to neighboring cells.
Furthermore, the scientists observed that the concentration and activity of Nrf2 in the skin drops the further from the surface it gets. This means the inner skin cells die more quickly under the influence of UVB than the outer ones – seemingly a paradox.
After all, you would expect the outer skin cells to be more exposed to the harmful impact of UVB radiation and thus succumb more rapidly than the inner ones, which also have to produce new skin cells through countless divisions. However, the new findings reveal that in actual fact the apparent paradox makes sense: The epidermis guarantees the skin’s integrity and, therefore, the upper layers have to remain intact, and this is achieved by the high levels of Nrf2 in these cells.
However, this is different for the skin stem cells in the innermost layer. As soon as these cells come into contact too intensely with UVB rays and suffer damage that is too extensive for the cell to repair, they have to die to prevent the damage from being passed on to its offspring. Normally, the lower cell layer is also protected by the Nrf2-expressing upper layers. If UVB radiation hits the skin, however, the level of protection in the inner layer is not sufficient and the cells die before too much damage can accumulate.
Broccoli extract against sun damage?
Other researchers had already shown that broccoli-sprout extracts protect the skin from UVB toxicity. Interestingly, the extract contains the substance sulforaphane, which activates Nrf2. Based on this and their own new findings, the scientists consider the activation of Nrf2 a useful strategy to limit the skin damage caused by UVB radiation.
“This mechanism is interesting as it could be used for pharmacologic intervention”, says Matthias Schäfer, a senior scientist in Sabine Werner’s group and first author of the study. However, he is skeptical about its potential use for sun protection at this stage; first it needs to be clarified how strongly and how often Nrf2 can be activated and what side effects this activation has. After all, observations in mice have revealed to the researchers that the skin becomes flaky upon increased activation of Nrf2. Nevertheless, the new results suggest that the development of better and more specific Nrf2 activators could constitute an important strategy in the protection against UV damage.
References and sources:
Schäfer M et al. Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis. Genes&Development 24: 1045-1058. Article published online. DOI:10.1101/gad.568810