Sir Peter Ratcliffe (Oxford University) has recently been announced as this year’s winner of the Nobel Prize in Physiology or Medicine alongside William Kaelin, Jr (Harvard University) and Gregg Semenza (Johns Hopkins University).
This prize was awarded for seminal work describing the mechanisms of oxygen sensing and control. The discovery centers on hypoxia-inducible factors (HIFs), a family of transcription factors that orchestrate cellular responses to hypoxia, thereby triggering metabolic, angiogenic and cell-cycle adaptations. In the wider physiological context, HIFs orchestrate erythropoietic and cardiopulmonary responses to hypoxia.
Under normoxic conditions, these HIF proteins are constantly produced then targeted for proteolytic degradation by the action of prolyl hydroxylases (PHDs). These enzymes act as oxygen sensors owing to their requirement for oxygen as a substrate. Sir Ratcliffe’s laboratory helped uncover the role of these enzymes and identified the sites at which HIFs are hydroxylated (1 , 2).
Beyond enhancing our understanding of basic homeostatic control, these discoveries have also had far-reaching translational applications, most notably that of inhibiting PHDs for the treatment of anaemia.
The interplay between oxygen and iron homeostasis has long been recognised. Sir Ratcliffe himself once declared that “HIF may as well be called iron deficiency-inducible factor”. Indeed, the PHDs that regulate HIF stability require iron as a co-factor. This is reflected in the pathophysiological manifestations of iron deficiency, that often mimic the body’s response to hypoxia, e.g. pulmonary arterial hypertension. Another important aspect of this interplay is the control of renal HIF2 by Iron Regulatory Proteins (IRPs), a mechanism that is thought to couple erythropoiesis to iron availability.
For those reasons, this Nobel prize is good news for those of us interested in iron. Over the coming years, we are likely to learn of further intersections between iron and oxygen homeostasis. The challenge will be to capitalise on these, so that iron-altering therapies could be harnessed to treat disorders of hypoxic signalling and vice versa. Another challenge for us in the iron community will be to raise the profile of iron research even further with a Nobel prize of our very own!
We are extremely pleased to announce that Sir Ratcliffe will be the keynote speaker at the upcoming European Iron Club meeting in Oxford, 2-5 September 2020. (EIC2020)
Contributed by Prof Samira Lakhal-Littleton, Department of Physiology, Anatomy & Genetics
University of Oxford