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Nonstructural protein 1 (nsp1) widespread RNA decay phenotype varies among Coronaviruses

ABSTRACT: Extensive remodeling of host gene expression by coronaviruses nsp1 proteins is a well-documented and conserved aspect of coronavirus-host takeover. Using comparative transcriptomics we investigate the diversity of transcriptional targets between nsp1 proteins between α- and β- coronaviruses. Additionally, Affinity Purification Mass-Spectrometry was implemented to identify common and divergent interactors between the nsp1 proteins. While we detected widespread RNA destabilization between the different nsp1s, closely related nsp1 showed little similarities in clustering of targeted genes. Partial overlapping transcriptional targeting between α-CoV 229E and MERS nsp1 may suggest a shared similar targeting mechanism, as MERS nsp1 preferentially targets nuclear transcripts. Our interactome data shows great variance between nsp1 interactions, with 229E nsp1, the smallest tested here, interacts with the most host proteins, while MERS nsp1 only engaged with a few. While nsp1 is a rather well-conserved protein with consistent functions across different coronaviruses, its precise effects on host cells is virus-specific.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217848 | GEO | 2022/11/17

REPOSITORIES: GEO

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Project description:Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV, and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) analysis for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.1 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3.1 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.

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Nonstructural protein 1 (nsp1) widespread RNA decay phenotype varies among Coronaviruses

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