Linking the unfolded protein response to oxygen sensing - A phosphoproteomic approach to identify novel substrates of the ER kinase PERK

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The unfolded protein response (UPR) is a process by which cells clear accumulations of misfolded and damaged proteins. Such accumulations are associated with a number of age-related diseases such as cancers and neurodegenerative disease. 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, eIF2a. As with misfolded protein accumulation, aberrant PERK signalling is associated with a variety of diseases. Also implicated in several human diseases is the cellular response to low oxygen. Recent work in the Kenneth lab 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. Using an unbiased phosphoproteomic screen and biochemical assays, we will first identify novel direct substrates of PERK. CRISPR experiments will then allow us to characterise the possible roles of these substrates in the regulation of the HIF-dependent response. Through this work we aim to further the understanding of the relationship between the UPR and hypoxia response, which may lead to targeted therapeutic strategies against pathologies related to misfolded protein accumulation.