Stress is needed for the production of haemoglobin levels in the blood, new research has found.
Researchers at the Hebrew University of Jerusalem, Israel, say that even at the cellular level, stress and the ability to mount a stress response are essential to survival.
Their study, published in the latest edition of Cell Research, reveals a new mechanism through which globin genes are expressed.
To produce a globin protein molecule, the DNA of the globin gene is first transcribed into a long RNA molecule from which internal segments must be spliced to generate the RNA template for protein synthesis in the red cell.
Professor Raymond Kaempfer, of the Hebrew University’s Faculty of Medicine, and colleagues found that for each of the adult and foetal globin genes, the RNA splicing is strictly controlled by an intracellular stress signal.
While the signal has been known about, Professor Kaempfer and his team found that the long RNAs transcribed from the globin genes each contain a short intrinsic RNA element, which can activate the enzyme PKR.
The PKR enzyme has to be activated in this way or the long RNA cannot be spliced to form the mature RNA template for globin protein synthesis.
Professor Kaempfer said: 'Surprisingly, we have revealed an entirely new mechanism through which haemoglobin gene expression is regulated by stress. An intracellular signal, essential for coping with stress, is absolutely necessary to allow for haemoglobin production. That stress signal is activated by the haemoglobin gene itself.
'Although we have long known that this signal strongly inhibits protein synthesis in general, during haemoglobin gene expression it first plays its indispensable, positive role before being turned off promptly to allow for massive haemoglobin formation needed for breathing.'
Once activated, PKR place a phosphate onto a key initiation factor needed for the synthesis of all proteins, called eIF2-alpha. That leads to inactivation of eIF2-alpha, which results in a block in protein synthesis. This process is essential for coping with stress.
They also discovered that once activated, PKR must phosphorylate eIF2-alpha, and that phosphorylated eIF2-alpha is essential to form the machinery needed to splice globin RNA.
Understanding that stress is essential may have important implications for understanding haemoglobin expression, said Prof Kaempfer.
'What this boils down to is that even at the cellular level, stress and the ability to mount a stress response are essential to our survival,' he added. 'We have long known this in relation to other biological processes, and now we see that it is at play even for the tiny molecules that carry oxygen in our blood.'
Source: Ilan L, Osman F, Namer LS et al. PKR activation and eIF2-alpha phosphorylation mediate human globin mRNA splicing at spliceosome assembly. Cell Research 4 April 2017; doi:10.1038/cr.2017.39
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