Linking the Unfolded Protein Response to oxygen sensing: A phosphoproteomic approach to identifying novel PERK substrates

The unfolded protein response (UPR) is a process by which cells clear accumulations of misfolded and damaged proteins. PERK, a kinase residing in the endoplasmic reticulum, has an essential role in the UPR. Activation of PERK halts global protein synthesis via the phosphorylation of the translation initiation factor, eIF2α. Aberrant PERK signalling is associated with a number of age-related diseases such as cancers and neurodegenerative disease. Also implicated in several human diseases is the cellular response to low oxygen. Our recent work has shown a role for PERK in the regulation of the hypoxia-inducible factor (HIF)-dependent hypoxia response, however, the pathway underlying this regulatory link remains unclear. We have shown that this effect is independent of the two known PERK substrates, eIF2α and Nrf2. We have therefore used phosphoproteomic mass spectrometry approaches to identify novel putative substrates of PERK, aiming to further elucidate the mechanism behind PERK-dependent control of HIF1α protein expression.