Abstract
Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. It allows production of essential viral, structural and replicative enzymes that are encoded in an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshift elements and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the SARS-CoV-2 frameshift element and the host proteome. We reveal that the short isoform of the zinc-finger antiviral protein (ZAP-S) is a direct regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and inhibits viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and interferes with the folding of the frameshift RNA element. Together, these data identify ZAP-S as a host-encoded inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.
Highlights
Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2
We explored whether transacting host or viral factors can modulate SARS-CoV-2 –1PRF
We discovered that the short isoform of the interferon-induced zinc-finger antiviral protein ZAP-S can strongly impair SARSCoV-2 frameshifting and decrease viral replication
Summary
Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. The stimulatory RNA element causes ribosomes to become trapped in an unusual conformation that is relieved by either the spontaneous unfolding of the blockade or by a –1 slip on the mRNA6,10 It is becoming clear, that cis-acting elements are not the only determinants of frameshifting in cells and that trans-acting viral and cellular factors as well as small molecules or oligonucleotides can alter frameshifting levels[11,12,13,14]. Despite these recent insights, fundamental questions remain unanswered. No cellular or viral factor has been reported to affect FE through that route
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