PhD Project "Molecular switches regulating stress granule oscillation" (Ruggieri_01) - Heidelberg University

Employer

Molecular Virology, Heidelberg University, Heidelberg, Germany

Description

Cells respond to a variety of environmental cues, including viral infection, by activating the integrated stress response (ISR), a central pathway that controls host protein synthesis [1]. Our previous research revealed that chronic infection with hepatitis C virus induces a unique temporal control of this pathway, with alternating off and on states of translation, accompanied by the assembly and disassembly of cytosolic stress granules, respectively [2,3]. This dynamic response is controlled through the phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) by two antagonistic switches: the stress kinase Protein Kinase R (PKR) activated by viral double-stranded RNA, and Growth Arrest and DNA Damage inducible 34 (GADD34), a regulatory subunit of protein phosphatase PP1 and central component in the ISR negative feedback loop to resume translation and avoid irreversible damage. Our recent results have established that GADD34 mRNA levels serve as the molecular memory of the activated ISR and set the threshold for cellular stress responsiveness and mediates adaptation to stress [4].

The goal of this PhD project is to investigate mechanisms by which cells fine-tune the GADD34 negative feedback loop to adjust the ISR sensitivity and achieve adaptation to stress. We will explore uncharacterized pathways that regulate GADD34 both at the mRNA and protein levels. To this end, we will address the role of upstream open reading frames and nonsense-mediated mRNA decay in GADD34 mRNA turnover, as well as GADD34 post-translational modifications whose functions have not yet been established.

The project benefits from a close, long-standing collaboration between the Stoecklin lab, focusing on RNA biology [5-8], and the Ruggieri lab, focusing on host responses to RNA viruses [1-4].

Candidate requirements

- Master degree in Biotechnology, Biochemistry, Molecular Biology or Molecular Sciences.
- Dedicated interest in RNA biology and strong scientific curiosity.
- Ability to work both independently and in a team.
- High motivation, reliability, and initiative.

Further details

Please read more under "Open PhD Positions" on: https://www.hbigs.uni-heidelberg.de

Possible start of employment: Tuesday, 01 October 2024.

Contract: Full-time, Fixed-term

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