Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell

Abstract

As obligate intracellular parasites with limited coding capacity, RNA viruses rely on host cells to complete their multiplication cycle. Viral RNAs (vRNAs) are central to infection. They carry all the necessary information for a virus to synthesize its proteins, replicate and spread and could also play essential non-coding roles. Regardless of its origin or tropism, vRNA has by definition evolved in the presence of host RNA Binding Proteins (RBPs), which resulted in intricate and complicated interactions with these factors. While on one hand some host RBPs recognize vRNA as non-self and mobilize host antiviral defenses, vRNA must also co-opt other host RBPs to promote viral infection. Focusing on pathogenic RNA viruses, we will review important scenarios of RBP-vRNA interactions during which host RBPs recognize, modify or degrade vRNAs. We will then focus on how vRNA hijacks the largest ribonucleoprotein complex (RNP) in the cell, the ribosome, to selectively promote the synthesis of its proteins. We will finally reflect on how novel technologies are helping in deepening our understanding of vRNA-host RBPs interactions, which can be ultimately leveraged to combat everlasting viral threats.

Keywords: Innate Immunity; RNA biology; RNA viruses; Technology; Viral RNA sensing; Viral Translation; Virology.

Fig. 1

Detection, Modification and Degradation of vRNA by Cellular RBPs. The figure depicts different vRNA structures recognized by host RBPs. vRNA is sensed by different families of receptors (e.g. RLRs, TLRs, PKR). vRNA is edited by ADARs and methylated by host METTL proteins (m⁶A) or viral methyl transferases (2′-O-me). vRNA can also be degraded by 5′-3′ or 3′-5′ exonucleases (e.g. XRN1 and RNA exosome respectively) or by endonucleases (e.g. Dicer).

Fig. 2

Cap v/s IRES-dependent Translation Initiation. Upper panel: The figure depicts Cap-dependent translation initiation mechanism. Capped RNA is recognized by EIF4F complex recruiting the 43S complex to the 5′UTR of mRNA. This is followed by scanning until a Start codon in encountered, followed by the formation of 80S ribosomes before elongation. Lower panel: Depicted are different modes of IRES-dependent translation (I, II, III and IV). Note the minimal requirement for initiation factors depending on IRES class.

Fig. 3

Cellular translation initiation arrest upon viral infection. The figure depicts different modes of translation initiation arrest caused by viral infection. In green, viral proteins or RNA structures that influence translation initiation are listed. These can either act on endogenous mRNAs, eIF4F, eIF2, eIF3 or the ribosomal subunits. In red are listed the four known cellular eIF2alpha kinases: GCN2, HRI, PERK and PKR.