Abstract
Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C-terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains. Much progress in recent years has contributed to a picture of nsP3, particularly through its HVD as a hub for interactions with host cell molecules, with multiple effects on the biology of the host cell at early points in infection. These and many future discoveries will provide targets for anti-viral therapies as well as strategies for modification of vectors for vaccine and oncolytic interventions.
Highlights
Alphaviruses are a group of enveloped positive-sense single-stranded RNA (ss(+)RNA) viruses and belong to the family Togaviridae
The relative levels of nsP3 associated with active RNA replication complexes and that in the larger cytoplasmic aggregates varies for the different alphaviruses, for example most of the nsP3 staining in Semliki Forest virus (SFV)-infected cells colocalizes with dsRNA, while a much smaller fraction does so in chikungunya virus (CHIKV)-infected cells, with most staining present in larger cytoplasmic aggregates
Binding of ssRNA was observed, as exemplified by the CHIKV nsP3 macro domain, and an early study showed that mutation at a single residue glycine 68 in Sindbis virus (SINV) nsP3, which was predicted to be residing in an active site, blocked the majority of nsP3 phosphorylation and the synthesis of viral minus sense RNA [89]
Summary
Alphaviruses are a group of enveloped positive-sense single-stranded RNA (ss(+)RNA) viruses and belong to the family Togaviridae. 2. Expression of the Non-Structural Polyprotein Is Regulated by the Presence of Opal Stop Codon at the nsP3/4 Junction in Some Alphaviruses. CHIKV-induced disease in mice was associated with the presence of the opal termination codon and independent from viral replication. This effect is, not conserved in all alphaviruses, as can be seen from experiments with different SFV strains. Infections with SFV A7(74) are avirulent in adult mice, as mentioned above but a recombinant A7(74) virus, having an Arg in place of the opal stop codon (rA774-arg), as in SFV4, shows increased pathogenicity, despite still being far less virulent than SFV4 or when the entire nsP3 was exchanged [38,39]. SFV, MAYV nsP3 contains the same last 6 residues of the degradation signal at its C-terminus and very similar sets of C-terminal residues are present in RRV nsP3 but their function as degradation signals needs further validation
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