Abstract
Positive-stranded (+)RNA viruses greatly exploit host cells to support viral replication. However, unlike many other pathogens, (+)RNA viruses code for only a limited number of genes, making them highly dependent on numerous co-opted host factors for supporting viral replication and other viral processes during their infections. This excessive dependence on subverted host factors, however, renders (+)RNA viruses vulnerable to host restriction factors that could block virus replication. Interestingly, cellular ATP-dependent DEAD-box RNA helicases could promote or inhibit the replication of Tomato bushy stunt virus (TBSV) replication. However, it is currently unknown what features make a particular DEAD-box helicase either pro-viral or antiviral. In this work, we succeeded in reversing the viral function of the antiviral DDX17-like RH30 DEAD-box helicase by converting it to a pro-viral helicase. We also turned the pro-viral DDX3-like RH20 helicase into an antiviral helicase through deletion of a unique N-terminal domain. We demonstrate that in the absence of the N-terminal domain, the core helicase domain becomes unhinged, showing altered specificity in unwinding viral RNA duplexes containing cis-acting replication elements. The discovery of the sequence plasticity of DEAD-box helicases that can alter recognition of different cis-acting RNA elements in the viral genome illustrates the evolutionary potential of RNA helicases in the arms race between viruses and their hosts, including key roles of RNA helicases in plant innate immunity. Overall, these findings open up the possibility to turn the pro-viral host factors into antiviral factors, thus increasing the potential antiviral arsenal of the host for the benefit of agriculture and health science.
Highlights
Positive-stranded (+)RNA viruses exploit host cells by co-opting many cellular factors to facilitate viral replication
It opens up the opportunity to generate new antiviral tools by converting pro-viral host factors into antiviral factors, enhancing our molecular tools against the ever-evolving RNA viruses
To identify what domains are responsible for the antiviral function of RH30 DEAD-box RNA helicase, we expressed deletion mutants of RH30 helicase in N. benthamiana plants via agroinfiltration
Summary
Positive-stranded (+)RNA viruses exploit host cells by co-opting many cellular factors to facilitate viral replication. The emerging picture is that the coopted host factors affect many steps of RNA virus replication. The assembly of membrane-bound viral replicase complexes (VRCs) is assisted by host translation initiation and elongation factors, protein chaperones, RNA-modifying enzymes, SNARE and ESCRT proteins, the actin network, and lipids [1,2,3,7,9,10]. The mechanistic roles of host factors in viral RNA replication is intensively studied with Tomato bushy stunt virus (TBSV) and other tombusviruses infecting plants. Several cis-acting replication elements have been defined in the TBSV (+) and (-) RNAs, which have critical functions in RNA template selection, RNA recruitment, in the assembly of VRCs, activation of the p92 RdRp and in viral RNA synthesis [13,14,15,16,17,18,19]
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