The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks

The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications. This review from Mircea and Kealin provides a historical perspective on prolyl hydroxylases and their HIF targets, and delves into the more complex role that feedback loops and noncoding RNAs play in sensing and regulating response to hypoxia.