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

Abstract

Extensive remodeling of the host gene expression environment by coronaviruses nsp1 proteins is a well-documented and conserved piece of the coronavirus-host takeover battle. However, whether and how the underlying mechanism of regulation or the transcriptional target landscape differ amongst coronaviruses remains mostly uncharacterized. In this study we use comparative transcriptomics to investigate the diversity of transcriptional targets between four different coronavirus nsp1 proteins (from MERS, SARS1, SARS2 and 229E). In parallel, we performed Affinity Purification followed by Mass-Spectrometry to identify common and divergent interactors between these different nsp1. For all four nsp1 tested, we detected widespread RNA destabilization, confirming that both β- and α- Coronavirus nsp1 broadly affect the host transcriptome. Surprisingly, we observed that even closely related nsp1 showed little similarities in the clustering of genes targeted. Additionally, we show that the RNA targeted by nsp1 from the α-CoV 229E partially overlapped with MERS nsp1 targets. Given MERS nsp1 preferential targeting of nuclear transcripts, these results may indicate that these nsp1 proteins share a similar targeting mechanism. Finally, we show that the interactome of these nsp1 proteins differ widely. Intriguingly, our data indicate that the 229E nsp1, which is the smallest of the nsp1 proteins tested here, interacts with the most host proteins, while MERS nsp1 only engaged with a few host proteins. Collectively, our work highlights that while nsp1 is a rather well-conserved protein with conserved functions across different coronaviruses, its precise effects on the host cell is virus-specific.

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

“…This strategy is surprisingly well conserved among related alpha-and gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) ORF37 (SOX), Herpes Simplex virus-1 (HSV-1) vhs, Epstein-Barr Virus (EBV) BGLF5, and the Murine Herpesvirus 68 (MHV68) muSOX [47][48][49]. There are also several RNA viruses that have evolved the same host-shutoff strategy, including several human coronaviruses and influenza A virus (IAV) [50][51][52]. Each of these viral endonucleases, though diverse in mechanism, ultimately trigger the internal cleavage of messenger RNA (mRNA) targets, rendering these transcripts susceptible to both 3 to 5 as well as 5 to 3 directional RNA decay machinery such as degradation by the major cellular exonuclease XRN1 [45].…”

Shiftless, A Critical Piece of the Innate Immune Response to Viral Infection

“…This strategy is surprising well conserved among related alpha-and gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) ORF37 (SOX), Herpes Simplex virus-1 (HSV-1) vhs, Epstein-Barr Virus (EBV) BGLF5, and the Murine Herpesvirus 68 (MHV68) muSOX [50][51][52]. There are also several RNA viruses that have evolved the same host-shutoff strategy, including several human coronaviruses and influenza A virus (IAV) [53][54][55]. Each of these viral endonucleases, though diverse in mechanism, ultimately trigger the internal cleavage of messenger RNA (mRNA) targets, rendering these transcripts susceptible to both 3' to 5' as well as 5' to 3' directional RNA decay machinery such as by the major cellular exonuclease XRN1 [48].…”