Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

The Castello lab, in collaboration with an international and multidisciplinary team, uncovered the interactions that SARS-CoV-2 RNA establishes with the host cell, many of which are fundamental for infection. These discoveries pave the way for the development of new therapeutic strategies for COVID-19 with broad-range antiviral potential. 

The genetic information of SARS-CoV-2 is encoded in an RNA molecule instead of DNA. The viral RNA is central to the SARS-CoV-2 life cycle, as it must be multiplied, translated, and packaged into new viral particles to produce the viral progeny. Despite the complexity of these processes, SARS-CoV-2 only encodes a handful of proteins able to engage with viral RNA. To circumvent this limitation SARS-CoV-2 hijacks cellular proteins and repurposes it for its own benefit. However, the identity of these proteins has remained unknown until now.
Researchers from the University of Oxford in collaboration with other labs across UK and Europe have developed a new approach to discover in a comprehensive manner the proteins that ‘stick’ to SARS-CoV-2 RNA in infected cells. With this method, authors uncovered that SARS-CoV-2 RNA hijacks more than a hundred cellular proteins, which appear to play critical roles in the viral life cycle. 
This work, published in Molecular Cell, identifies many potential therapeutic targets with hundreds of available drugs targeting them. In a proof-of-principle experiment, authors selected four drugs targeting four different cellular proteins. These drugs caused from moderate to strong effects in viral replication. 

‘These exciting results are only the beginning – said Alfredo Castello, one of the researchers that has led the work -. With hundreds of compounds that target these critical cellular proteins, it will be possible to identify novel antivirals. Our efforts, together with those of the scientific community, should focus now on testing these drugs in infected cells and animal models to uncover which ones are the best antivirals.’  

An unexpected observation of this study is that viruses from different origin such as SARS-CoV-2 and Sindbis, hijack a similar repertoire of cellular proteins. This discovery is very important, as cellular proteins with important and wide-spread roles in virus infection have potential as target for broad-spectrum antiviral treatments.

‘In this stage of the pandemic in which vaccines have proved their value – added Alfredo Castello – it becomes fundamental to develop new therapeutic approach to counteract emergent vaccine-resistant variants or novel pathogenic viruses with pandemic potential’.  
Professor Shabaz Mohammed adds: ‘These new methods to discover the interactors of viral RNA builds on nearly 6 years of joined effort between the Castello and Mohammed labs using Sindbis virus as discovery model. This pre-existent work allowed us to react rapidly at the beginning of the COVID-19 pandemic and study the interactions between SARS-CoV-2 and the host cell in a reduced timeframe. Our methodology will now be ready to respond rapidly to future viral threads.’  

The paper ‘Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection’ is published in the journal Molecular Cell. The work was led by Dr Wael Kamel and Marko Noerenberg, postdoctoral researchers at Glasgow and Oxford, and Berati Cerikan, postdoctoral fellow at the University of Heidelberg.

Additional Information
The following videos have been posted on social media and explains this research in an accessible way:
sarscov2_per_movie.m4v

Opportunities to join the Castello lab as PhD student

New opportunities to do your PhD studies in the Castello lab. We are looking for motivated students to characterise the roles of the exonuclease XRN1 and the new antiviral factor GEMIN5 in virus infection. The students will employ a broad range of high-throughput techniques (RNAseq, proteomics), state-of-the-art virology methods and computational approaches to elucidate the roles of these RNA binding proteins for a variety of viruses, including SARS-CoV-2. If you are interested, do not hesitate to contact us .

The Castello lab is eligible from the MVLS doctoral trining programmes and the MRC DTP Precision Medicine.

When cellular proteins meet SARS-CoV-2 RNA: a story of protein-RNA interactions

I our recent work we comprehensively and systematically identify the complement of cellular RNA-binding proteins that are involved in SARS-CoV-2 infection. We discover that the cellular RNA-binding proteome (RBPome) is pervasively remodelled upon SARS-CoV-2 infection, affecting a broad range of RNA metabolism and antiviral pathways. We also apply a new method to uncover the composition of SARS-CoV-2 RNPs, revealing a dozens of cellular RBPs and seven viral proteins. Our study reveals a new universe of host-virus interactions awaiting to be characterised and with great potential for novel therapies againt COVID-19.

This work is a synergistic collaboration between the Castello, Mohammed, Bartenschlager, Martinez and Lilley labs. See full publication in BioRxiv below:

Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection | bioRxiv

Moving to the MRC-University of Glasgow Centre for Virus Research

The Castello lab will move to the Centre of Virus Research (CVR), in the University of Glasgow, between Nov 2020 and July 2021. The CVR is home to the UK’s largest critical mass of virology researchers, co-located in a purpose-built centre with state-of-the art facilities and infrastructure. New research activities will be based at the CVR, including new PhD and Msc projects.      

The CVR research covers emerging viruses, chronic infections , innate and intrinsic immunity , viruses and cancer, structural virology, viral genomics and bioinformatics.

The CVR is a member of the COVID-19 genomics UK consortium, which is currying out critical research to follow the expansion of SARS-Cov-2 and the consequent evolution of its genome. The CVR contribution to combat COVID-19 pandemics spans different lines of research, including virus tracking, characterisation and surveillance, as well as development of critical toolkit to enable UK research in SARS-Cov-2.

Follow the CVR in twitter: @CVRinfo

Discovering the RNA-Binding Proteome of Plant Leaves with an Improved RNA Interactome Capture Method

RBPs are key key drivers of gene expression by controlling RNA fate. However, our knowledge about RBPs in plants is very limited. I our recent work, we report an improved RNA interactome capture approach to discover RNA-binding proteins (RBPs) in plant leaves . Using this ‘plant-adapted RNA interactome capture’ (ptRIC) we have identified hundreds novel RBPs, including many enzymes and proteins from the photosynthetic apparatus. ptRIC did not only allowed the generation of the deepest ‘RBPome’ of plant tissue to date, but also opens the possibility to study how the RBPome remodels in response to environmental, physiological and pathological cues.

This work is an interdisciplinary collaborative effort between the Castello lab (Department of Biochemistry) and Preston lab (Department of Plant Sciences) at the University of Oxford. Find out more about this work here:

Discovering the RNA-binding proteome of plant leaves with an improved RNA interactome capture method. Marcel Bach-Pages, Felix Homma, Jiorgos Kourelis, Farnusch Kaschani, Shabaz Mohammed, Markus Kaiser, Renier A. L. van der Hoorn, Alfredo Castello*, Gail M. Preston*

Written by Marcel Bach-Pages