The SARS-CoV-2 RNA interactome

SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host RNA-binding proteins (RBPs) and to evade antiviral RBPs. To uncover the SARS-CoV-2 RNA interactome, we here develop a robust ribonucleoprotein (RNP) capture protocol and identify 109 host factors that directly bind to SARS-CoV-2 RNAs. Applying RNP capture on another coronavirus, HCoV-OC43, revealed evolutionarily conserved interactions between coronaviral RNAs and host proteins. Transcriptome analyses and knockdown experiments delineated 17 antiviral RBPs, including ZC3HAV1, TRIM25, PARP12, and SHFL, and 8 proviral RBPs, such as EIF3D and CSDE1, which are responsible for co-opting multiple steps of the mRNA life cycle. This also led to the identification of LARP1, a downstream target of the mTOR signaling pathway, as an antiviral host factor that interacts with the SARS-CoV-2 RNAs. Overall, this study provides a comprehensive list of RBPs regulating coronaviral replication and opens new avenues for therapeutic interventions. [Display omitted] •We identify viral and host proteins that directly interact with coronavirus RNAs•Comparison of SARS-CoV-2 and HCoV-OC43 shows conservation of coronavirus RNA interactome•This reveals 17 antiviral factors such as LARP1, ZC3HAV1, TRIM25, PARP12, and SHFL•We also uncover 9 proviral factors hijacked by SARS-CoV-2, including EIF3D and CSDE1 By capturing the ribonucleoprotein (RNP) complex of two coronaviruses SARS-CoV-2 and HCoV-OC43, Lee et al. provide an unbiased and comprehensive list of RNA-binding proteins that physically interact with the viral genome and transcriptome. Loss-of-function experiments stratified the host factors into either proviral or antiviral groups, offering a RNA-centric perspective for understanding the life cycle of coronavirus.