Human antigen R differentially modulates the translation of SARS-CoV-2 genomic and sub-genomic RNAs

Abstract

AbstractSevere acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA associates with different RNA-binding host proteins at each stage of its life cycle, although the potential role of human antigen R (HuR) is unclear. Here, we found that HuR bound the 5′-untranslated region (5′-UTR) of SARS-CoV-2, and knockdown and knockout studies revealed the importance of such binding in viral translation. We identified 5′-UTR mutations in SARS-CoV-2 variants of concern that altered the HuR-binding affinity. Interestingly, HuR promoted non-structural protein translation through the genomic 5′-UTR and suppressed the structural protein translation from the sub-genomic 5′-UTR, which required polypyrimidine tract-binding protein binding to the 5′-UTR. HuR knockout increased the sensitivity to remdesivir treatment by decreasing its half-maximal inhibitory concentration by 10-fold. An antisense oligonucleotide (whose binding site overlapped the HuR-binding site) reduced viral RNA production and viral titers in wild-type cells but not HuR-knockout cells, further suggesting that HuR binds the SARS-CoV-2 5′ UTR and promotes replication. Our results indicate that HuR supports SARS-CoV-2 life cycle by promoting differential translational reprogramming of genomic and sub-genomic RNAs, implying that HuR can potentially be targeted for therapeutic interventions.