Uncovering a new universe of host-virus interactions driven by cellular RNA-binding proteins

Supervisor: Prof Alfredo Castello, School of Infection & Immunity 

 

Rotation Project:

RNA is a central molecule in the life cycle of RNA viruses, acting not only as mRNA, but also as a genome. It is thus unsurprising that viral RNA serves a hub for critical host-virus interactions in infected cells. However, the complement of cellular proteins that engage with viral RNA has remained largely unknown. In the last years, the Castello lab has made important advances towards elucidating the interactome of the viral RNA through the development of novel proteome-wide approaches to study protein-RNA interactions in infected cells. These new approaches have been applied to several key viral models, including HIV-1 and SARS-CoV-2. Our studies revealed a new universe of host-virus interactions with critical roles promoting or restricting infection. These new host-virus interactions thus hold great potential for the development of novel broad-spectrum antiviral therapies.

The PhD projects in the Castello lab will build on these important discoveries, aiming to answer the following fundamental questions:

  • How much the viral RNA interactome differ across viruses and host cells?
  • What is the architecture of these interactions?
  • How do cellular proteins recognise the viral RNA?
  • What are the molecular mechanisms by which these critical host-virus interactions control the viral life cycle?
  • Can these cellular proteins be exploited as targets for antiviral therapies?  

To answer these questions, the PhD student will apply multidisciplinary approaches, spanning cellular and molecular biology, RNA biology, virology, OMICS and computational sciences. Moreover, our research will involve national and international collaborations with world-leading researchers in complementary areas of research.

REFERENCES

  1. Uncovering viral RNA-host cell interactions on a proteome-wide scale. Iselin, L., Palmalux, N., Kamel, W., Simmonds, P., Mohammed, S., anf Castello, A. TIBS. 2022. https://doi.org/10.1016/j.tibs.2021.08.002
  2. A prenylated dsRNA sensor protects against severe COVID-19. Winckenhagen, A., Science. 2021. https://doi.org/10.1126/science.abj3624
  3. Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection. Kamel, W., Noerenberg, M., Cerikan, B., […], Bartenschlager R., Mohammed, S., Castello, A.* Mol Cell. 2020. https://doi.org/10.1016/j.molcel.2021.05.023
  4. Global analysis of RNA-binding protein dynamics by comparative and enhanced RNA interactome capture. Perez-Perri, J.I., Noerenberg, M., […], S., Hentze, M.W. and Castello, A.*. Nature Prot. 2021 Jan;16(1):27-60
  5. System-wide profiling of RNA-binding proteins uncovers key regulators of virus infection. Garcia-Moreno M, Noerenberg M, […], Mohammed S and Castello A*. Mol Cell. 2019 Feb 21. pii: S1097-2765(19)30037-1. doi: https://doi.org/10.1016/j.molcel.2019.01.017