[Source: Journal of Virology, full page: (LINK). Abstract, edited.]
Schlafen 11 Restricts Flavivirus Replication.
Federico Valdez, Julienne Salvador, Pedro M. Palermo, Jonathon E. Mohl, Kathryn A. Hanley, Douglas Watts, Manuel Llano
Schlafen 11 (Slfn11) is an interferon-stimulated gene that controls synthesis of proteins by regulating tRNA abundance. Likely through this mechanism, Slfn11 has previously been shown to impair human immunodeficiency virus 1 (HIV-1) infection and the expression of codon-biased open reading frames. Because replication of positive-sense single-stranded RNA [(+)ssRNA] viruses requires the immediate translation of the incoming viral genome whereas negative-sense, single-stranded RNA [(-)ssRNA] viruses carry at infection an RNA replicase that makes multiple translation competent copies of the incoming viral genome, we reasoned that (+)ssRNA viruses will be more sensitive to the effect of Slfn11 on protein synthesis than (-)ssRNA viruses. To evaluate this hypothesis, we tested the effects of Slfn11 on the replication of a panel of ssRNA viruses in the human glioblastoma cell line A172, which naturally expresses Slfn11. Depletion of Slfn11 significantly increased the replication of (+)ssRNA viruses from the Flavivirus genus, including West Nile (WNV), dengue (DENV), and Zika virus (ZIKV) but had no significant effect on the replication of the (-)ssRNA viruses vesicular stomatitis (VSV, Rhabdoviridae family) and Rift Valley fever (RVFV, Phenuiviridae family). Quantification of the genome-containing viral particles to plaque forming units ratio indicated that Slfn11 impairs WNV infectivity. Intriguingly, Slfn11 prevented WNV-induced down-regulation of a subset of tRNAs implicated in the translation of 11.8% of the viral polyprotein. Low abundance tRNAs might promote optimal protein folding and enhance viral infectivity, as previously reported. In summary, this study demonstrates that Slfn11 restricts flavivirus replication by impairing viral infectivity.
We provide evidence that the cellular protein Schlafen 11 (Slfn11) impairs replication of flaviviruses, including West Nile (WNV), dengue (DENV), and Zika virus (ZIKV). However, replication of single-stranded, negative RNA viruses was not affected. Specifically, Slfn11 decreases the infectivity of WNV potentially by preventing virus-induced modifications of the host tRNA repertoire that could lead to enhanced viral protein folding. Furthermore, we demonstrated that Slfn11 is not the limiting factor of this novel broad anti-viral pathway.
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Keywords: Flavivirus; Zika virus; WNV; Dengue fever; Interferons.