Scientists Startled to Find Stress Is Crucial to Hemoglobin Production

Stress was known to shut down protein production in our cells. But the bad boy of physiology turns out to be essential to life in yet another way.

Where stress works in our favor:  Red blood cells, where hemoglobin is made, which turns out to be contingent on the appropriate stress signal inside the cells.

Stress is our friend, not a sentence you read every day. Scientists have now shown, to their own surprise, that stress is crucial to the production of hemoglobin in our red blood cells, which is in turn essential to life itself.

Oxygen is critical for all life except anaerobic bacteria that utilize sulfur atoms instead, for instance; viruses, which arguably aren't even a life form; and weird tiny animals called Loriciferans who live in the Mediterranean seabed whose metabolism remains an enigma. We breathe in oxygen, which gets taken up by the hemoglobin in our red blood cells, and whisked to all other cells in our bodies.

Hemoglobin is produced by red blood cells in our bone marrow. Until now, explains Prof. Raymond Kaempfer of the Hebrew University of Jerusalem, molecular biologists had assumed hemoglobin's production to be straightforward: DNA is translated into RNA which is translated into a protein. Not so.

To be clear, it isn't the stress itself that we need to make hemoglobin. It's the molecular effect of stress, and how that regulates hemoglobin production.

The amazing thing is that when the long hemoglobin gene is translated into a long RNA molecule in red blood cells, that long RNA molecule turns on the same response in the cell that is turned on by stress.

The cell's stress response is turned on by any sort of stress, really, not just the body feeling stressed for oxygen – running, starvation, heat, the boss, dreaming of being eaten by rats. Whatever else it does, that stress response includes shutting down the cell's protein production.

Now we realize that translation of the globin gene in red blood cells evokes that very same stress response.

How is that helpful, given that the stress response shuts down protein production?

The weird bit is that the cellular stress response shuts down protein production, but it also splices that long hemoglobin RNA molecule into a shorter hemoglobin RNA molecule.

Red blood cells, where hemoglobin is made.
Janice Haney Carr, AP

Unlike the longer hemoglobin RNA molecule, the shorter hemoglobin RNA molecule cannot evoke the stress response. So the stress response in the red blood cell stops. The cell can produce protein again, and the protein that it produces, being a red blood cell, is, 95% of the time, hemoglobin. Ta da!

In case you want to know, the intracellular stress signal involves an enzyme called PKR, which is present in every cell of the body. Until now, scientists had thought PKR specifically was only activated by virus RNA. No! Kaempfer and the team found the long hemoglobin RNAs strongly activate PKR, and when PKR is activated, it inhibits a molecule essential for protein production, called eIF2-alpha. But – phosphorylated eIF2-alpha turns out to be crucial to splicing the long hemoglobin RNAs, to form the mature RNA from which hemoglobin is synthesized. Now you know.

"Nobody ever suspected that same stress mechanism might have a second opposite role – being absolutely needed for positive expression rather than inhibit the synthesis of protein," Kaempfer told Haaretz. "The established role of stress response was a negative control; what we discovered is that it is a positive control as well."