1. Co-translational quality control and its role in neural tissue
Annotation:
Ribosome-associated quality control (RQC) is crucial for degrading truncated nascent proteins produced on aberrant mRNAs. Mutations in RQC components cause neurodegeneration both in animal models and human patients. Moreover, RQC insufficiency and subsequent protein aggregation critically contribute to proteostasis impairment and systemic decline during ageing.
The successful candidate will utilize a multidisciplinary approach to provide detailed mechanistic understanding of the critical human RQC system in combination with an in vivo study to reveal processes leading to RQC-driven pathological changes in neural tissue. He/she will utilize human cell cultures, protein expression and purification techniques and biochemistry methods to produce samples for cryogenic electron microscopy (cryo-EM). Comprehensive training in cryo-EM will be available to the successful candidate. The candidate will also have a unique opportunity to acquire expertise in the use of C. elegans as a model organism during a research stay at a collaborating laboratory in Bolzano (Italy).
Recommended literature:
- Tesina, P., et al., Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control. Mol Cell, 2023. 83(4): p. 607-621 e4.
- Lu, B., Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection. Front Cell Dev Biol, 2022. 10: p. 970654.
- Filbeck, S., et al., Ribosome-associated quality-control mechanisms from bacteria to humans. Mol Cell, 2022. 82(8): p. 1451-1466.
- Udagawa, T., et al., Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival. Cell Rep, 2021. 34(1): p. 108599.
- Aviner, R., et al., Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease. bioRxiv, 2022: p. 2022.05.04.490528.
2. Translation in the context of human host-pathogen interaction
Annotation:
Proteins are produced by ribosome-catalyzed translation of mRNAs in all domains of life. Translation is also critical in the context of human host-pathogen interaction where the ribosome, as the central molecular machine for genetic information expression, is the subject to numerous regulatory and quality control events and pathological interventions. The strategies adopted by viruses to reprogram translation and co-translational quality control machinery to promote infection are poorly understood. Thus, there is an urgent need for further research in this area to develop effective strategies for combating viral infections.
The successful candidate will study how viruses affect human translation and co-translational quality control with the aim of providing high-resolution structures of large macromolecular assemblies. He/she will utilize human cell cultures, protein expression and purification techniques and biochemistry methods to produce samples for cryogenic electron microscopy (cryo-EM). Comprehensive training in cryo-EM will be available to the successful candidate.
Recommended literature:
- Xu, Z., et al., SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. Proc Natl Acad Sci U S A, 2022. 119(32): p. e2204539119.
- Liu, J., et al., Remodeling of the Ribosomal Quality Control and Integrated Stress Response by Viral Ubiquitin Deconjugases. 2023.
- Hsu, J.C., et al., Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication. Mol Cell, 2022. 82(9): p. 1631-1642 e6.
- Thoms, M., et al., Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science, 2020. 369(6508): p. 1249-1255.
- Lu, B., Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection. Front Cell Dev Biol, 2022. 10: p. 970654.
Requirements on candidates:
The ideal candidate should have a background in either molecular biology, biochemistry or structural biology. Experience with human cell culture work or protein biochemistry is a plus.
