ZMBH Open PhD positions

Open PhD positions

Molecular switches regulating stress granule oscillation during RNA virus infection

Project Leader: Georg Stoecklin

Stress granules (SGs) are cytosolic aggregates of stalled translation pre-initiation complexes that form under various stress conditions, including virus infection. SGs participate in controlling protein synthesis and are generally thought to have a cytoprotective function. Recently, we discovered that infection with hepatitis C virus (HCV) and other RNA viruses induces an oscillating host cell stress response characterized by cycles of SG assembly and disassembly (1). We identified protein kinase K (PKR) and GADD34 as two main switches that regulate SG oscillation by controlling the phosphorylation status of eIF2. The goal of this project is to quantify the spatio-temporal expression of GADD34 and provide experimental evidence for its oscillation using live-cell imaging microscopy. Moreover, the successful applicant will characterize novel candidate kinases identified in a screen as potential regulators of SG oscillation during HCV infection, including kinases involved in cell cycle control and inflammation. An important goal of the project is to determine whether SGs serve an anti- or pro-vial function during chronic HCV infection. The project is embedded within the larger activities of the lab in exploring RNA turnover (2), translation (3) and stress responses (4).

References:

(1) Ruggieri, A., Dazert, E., Metz, P., Hofmann, S., Bergeest, J.-P., Mazur, J., Bankhead, P., Hiet, M.-S., Kallis, S., Alvisi, G., Samuel, C.E., Lohmann, V., Kaderali, L., Rohr, K., Frese, M., Stoecklin, G. & Bartenschlager, R. Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 12:71-85 (2012). (2) Leppek, K, Schott, J, Reitter, S, Poetz, F, Hammond, MC & Stoecklin, G (2013) Roquin Promotes Constitutive mRNA Decay via a Conserved Class of Stem-Loop Recognition Motifs. Cell 153:869-881. (3) Schott, J, Reitter, S, Philipp, J, Haneke, K, Schafer, H & Stoecklin, G (2014) Translational regulation of specific mRNAs controls feedback inhibition and survival during macrophage activation. PLoS Genet 10:e1004368. (4) Hofmann, S, Cherkasova, V, Bankhead, P, Bukau, B & Stoecklin, G (2012) Translation suppression promotes stress granule formation and cell survival in response to cold shock. Mol Biol Cell 23:3786-3800.

Methods that will be used:

Live cell microscopy, genome-wide translation analysis, deep sequencing of RNA, CRISPR-mediated genome engineering, protein and RNA detection methods

Cooperation partners:

This is a collaborative project with Alessia Ruggieri (https://www.klinikum.uni-heidelberg.de/AG-Ruggieri.135585.0.html), and the successful applicant will have the opportunity to work in both labs. The project is embedded within the Heidelberg-Berlin Transregio TRR 186 „Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission“, funded by the DFG.

Personal qualifications:

We are looking for a highly motivated and interactive PhD student with a strong background in cellular and molecular biology.

Keywords:

RNA virus, stress response, RNA granule, cell cycle, inflammation, translation, kinase, signaling

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