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

未折叠蛋白反应（UPR）是细胞清除错误折叠和受损蛋白积累的过程。这种积累与许多与年龄有关的疾病，如癌症和神经退行性疾病有关。PERK是一种存在于内质网中的激酶，在UPR中起重要作用。PERK的激活通过翻译起始因子eIF2a的磷酸化阻止了全局蛋白的合成。与错误折叠蛋白积累一样，异常PERK信号与多种疾病有关。细胞对低氧的反应也与几种人类疾病有关。Kenneth实验室最近的研究表明，PERK在缺氧诱导因子（HIF）依赖性缺氧反应的调控中发挥作用，然而，这种调控联系背后的途径尚不清楚。使用无偏磷蛋白质组学筛选和生化分析，我们将首先确定PERK的新的直接底物。然后，CRISPR实验将使我们能够描述这些底物在hif依赖性反应的调节中可能发挥的作用。通过这项工作，我们的目标是进一步了解UPR和缺氧反应之间的关系，这可能导致针对错误折叠蛋白积累相关病理的靶向治疗策略。

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.