Unconventional RNA-binding proteins step into the virus-host battlefront

Abstract

The crucial participation of cellular RNA-binding proteins (RBPs) in virtually all steps of virus infection has been known for decades. However, most of the studies characterizing this phenomenon have focused on well-established RBPs harboring classical RNA-binding domains (RBDs). Recent proteome-wide approaches have greatly expanded the census of RBPs, discovering hundreds of proteins that interact with RNA through unconventional RBDs. These domains include protein-protein interaction platforms, enzymatic cores, and intrinsically disordered regions. Here, we compared the experimentally determined census of RBPs to gene ontology terms and literature, finding that 472 proteins have previous links with viruses. We discuss what these proteins are and what their roles in infection might be. We also review some of the pioneering examples of unorthodox RBPs whose RNA-binding activity has been shown to be critical for virus infection. Finally, we highlight the potential of these proteins for host-based therapies against viruses. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.

Keywords: RBPome; RNA; RNA interactome capture; RNA metabolism; RNA-binding domain; RNA-binding protein; infection; translation; virus.

Figure 1

RNA‐binding proteome (RBPome) implicated in virus infection and immunity. (a) Classification by RNA‐binding domain (i.e., classical, nonclassical, and other) of RNA‐binding proteins (RBPs) in different datasets: human RNA interactome capture (RNA‐IC); RNA‐IC linked to virus by gene ontology (GO) terms; RNA‐IC linked to virus by literature mining (LM); RNA‐IC linked to virus by GO and LM. (b) Word cloud of protein domains present in all virus‐linked RBPs. (c) STRING protein network showing connections between all virus‐linked RBPs. ER, endoplasmic reticulum

Figure 2

Virus‐linked RNA‐binding proteins (RBPs) with nonclassical or other RNA‐binding domains (RBDs). (a and c) Word cloud of protein domains present in nonclassical (a) and other (c) virus‐linked RBPs. (b and d) STRING protein network showing connections between nonclassical (b) and other (d) virus‐linked RBPs. ER, endoplasmic reticulum; F‐bP, fructose‐biphosphate; PPI, peptidyl‐prolyl cis–trans isomerase

Figure 3

RNA‐binding domains (RBDs) of virus‐related RNA‐binding proteins. RBDmap profiles of ILF3 (a), TRIM25 (b), and ILF2 (c). Boxes represent high confidence (red, 1% FDR) or relevant candidate (orange, 10% FDR) RBDs. White boxes symbolize Pfam‐annotated domains. Green lines indicate predicted disordered regions (IUPred score > 0.4). FDR, false discovery rate

Figure 4

RNA‐binding domains (RBDs) of virus‐related RNA‐binding proteins. RBDmap profiles of SEC31A (a), SEC61B (b), and SEC62 (c). Boxes represent high confidence (red, 1% FDR) or relevant candidate (orange, 10% FDR) RBDs. White boxes symbolize Pfam‐annotated domains. Green lines indicate predicted disordered regions (IUPred score > 0.4). FDR, false discovery rate