RNA binding proteins and RNA viruses: A journey together

Abstract

The interplay between viruses and host cells is extremely complex, as is the resulting disease dynamics. In the cytoplasm of host cells, (+) ss viral RNAs interact with numerous RNA-binding proteins (RBPs).
Work from our laboratory has shown that HuR, an RBP with multiple functions in RNA processing and translation, relocalizes from the nucleus to the cytoplasm upon Hepatitis C virus (HCV) infection. We have shown that two viral proteins, NS3 and NS5A, act co-ordinately to alter the equilibrium of the nucleo-cytoplasmic movement of HuR. NS3 activates protein kinase C (PKC)-δ, which in turn phosphorylates HuR on S318 residue, triggering its export to the cytoplasm. NS5A inactivates AMP-activated kinase (AMPK) resulting in diminished nuclear import of HuR through blockade of AMPK-mediated phosphorylation and acetylation of importin-α1.
In parallel, we have shown that HuR binds to SARS-CoV-2 5’UTR. The knock-down and knock-out of HuR reduced viral RNA levels and viral titres. Using an antisense strategy, we were able to reduce the viral RNA level in wildtype cells but not in HuR-knockout cells. Interestingly, results suggest HuR supports SARS-CoV-2 life by promoting differential translational reprogramming of both genomic and subgenomic RNAs.
Taken together, we demonstrate important roles of an RNA binding protein HuR, in two RNA viruses, HCV and SARS-CoV-2, and explored different ways to target it for tackling virus infections.