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  • Title: Alphavirus nsP3 functions to form replication complexes transcribing negative-strand RNA.
    Author: Wang YF, Sawicki SG, Sawicki DL.
    Journal: J Virol; 1994 Oct; 68(10):6466-75. PubMed ID: 8083984.
    Abstract:
    The alphavirus mutant Sindbis virus HR ts4, which has been assigned to the A complementation group, possessed a selective defect in negative-strand synthesis that was similar although not identical to that observed for the B complementation group mutant ts11 (Y.-F. Wang, S. G. Sawicki, and D. L. Sawicki, J. Virol. 65:985-988, 1991). The causal mutation was identified as a change of a C to a U residue at nucleotide 4903 in the nsP3 open reading frame that predicted a change of Ala-268 to Val. Thus, both nsP3 and nsP1 play a role selectively in the transcription of negative strands early in infection. The assignment of the mutation carried by an A complementation group mutant of Sindbis virus HR to nsP3 was unexpected, as mutations in other A complementation group mutants studied to date mapped to nsP2. Another mutant with a conditionally lethal mutation, ts7 of the G complementation group, also possessed a causal mutation resulting from a single-residue change in nsP3. Negative-strand synthesis ceased more slowly after a shift to the nonpermissive temperature in ts7-than in ts4-infected cells, and ts7 complemented ts11, but ts4 did not. However, the nsP3 of both ts4 and ts7 allowed reactivation of negative-strand synthesis by stable replication complexes containing nsP4 from ts24. Therefore, mutations in nsP3 affected only early events in replication and probably prevent the formation and/or function of the initial replication complex that synthesizes its negative-strand template. Because neither ts4 nor ts7 complemented 10A complementation group mutants, the genes for nsP2 and nsP3 function initially as a single cistron. We interpret these findings and present a model to suggest that the initial alphavirus replication complex is formed from tightly associated nsP2 and nsP3, perhaps in the form of P23, and proteolytically processed and trans-active nsP4 and nsP1.
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