PT  - JOURNAL ARTICLE
AU  - Joy S. Xiang
AU  - Jasmine R. Mueller
AU  - En-Ching Luo
AU  - Brian A. Yee
AU  - Danielle Schafer
AU  - Jonathan C. Schmok
AU  - Frederick E. Tan
AU  - Katherine Rothamel
AU  - Rachael N. McVicar
AU  - Elizabeth M. Kwong
AU  - Krysten L. Jones
AU  - Hsuan-Lin Her
AU  - Chun-Yuan Chen
AU  - Anthony Q. Vu
AU  - Wenhao Jin
AU  - Samuel S. Park
AU  - Phuong Le
AU  - Kristopher W. Brannan
AU  - Eric R. Kofman
AU  - Yanhua Li
AU  - Alexandra T. Tankka
AU  - Kevin D. Dong
AU  - Yan Song
AU  - Aaron F. Carlin
AU  - Eric L. Van Nostrand
AU  - Sandra L. Leibel
AU  - Gene W. Yeo
TI  - Discovery and functional interrogation of SARS-CoV-2 protein-RNA interactions
AID  - 10.1101/2022.02.21.481223
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.21.481223
4099  - http://biorxiv.org/content/early/2022/02/24/2022.02.21.481223.short
4100  - http://biorxiv.org/content/early/2022/02/24/2022.02.21.481223.full
AB  - The COVID-19 pandemic is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The betacoronvirus has a positive sense RNA genome which encodes for several RNA binding proteins. Here, we use enhanced crosslinking and immunoprecipitation to investigate SARS-CoV-2 protein interactions with viral and host RNAs in authentic virus-infected cells. SARS-CoV-2 proteins, NSP8, NSP12, and nucleocapsid display distinct preferences to specific regions in the RNA viral genome, providing evidence for their shared and separate roles in replication, transcription, and viral packaging. SARS-CoV-2 proteins expressed in human lung epithelial cells bind to 4773 unique host coding RNAs. Nine SARS-CoV-2 proteins upregulate target gene expression, including NSP12 and ORF9c, whose RNA substrates are associated with pathways in protein N-linked glycosylation ER processing and mitochondrial processes. Furthermore, siRNA knockdown of host genes targeted by viral proteins in human lung organoid cells identify potential antiviral host targets across different SARS-CoV-2 variants. Conversely, NSP9 inhibits host gene expression by blocking mRNA export and dampens cytokine productions, including interleukin-1α/β. Our viral protein-RNA interactome provides a catalog of potential therapeutic targets and offers insight into the etiology of COVID-19 as a safeguard against future pandemics.Competing Interest StatementJ.S.X, F.E.T, J.C.S and G.W.Y declare a pending patent application. ELVN is co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Eclipse BioInnovations. ELVN's interests have been reviewed and approved by the Baylor College of Medicine in accordance with its conflict-of-interest policies. The authors declare no other competing interests.