Schlafen 11 Restricts Flavivirus Replication

Abstract

21Schlafen 11 (Slfn11) is a ubiquitously expressed interferon stimulating gene (ISG) that 22 controls synthesis of proteins by regulating tRNA abundance. Likely through this 23 mechanism, Slfn11 has previously been shown to impair human immunodeficiency virus 24 1 (HIV-1) infection and the expression of codon-biased open reading frames. Because 25 replication of positive-sense single-stranded RNA [(+)ssRNA viruses] requires the 26 immediate translation of the incoming viral genome whereas negative sense, single 27 stranded [(-)ssRNA] viruses carry at infection an RNA replicase that makes multiple 28 translation competent copies of the incoming viral genome, we reasoned that (+)ssRNA 29 viruses will be more sensitive to the effect of Slfn11 on protein synthesis than (-)ssRNA 30 viruses. To evaluate this hypothesis, we tested the effects of Slfn11 on the replication of 31 a panel of ssRNA viruses in the human glioblastoma cell line A172, which naturally 32 expresses Slfn11. Depletion of Slfn11 in this cell line significantly increased the 33 replication of (+)ssRNA viruses from the Flavivirus family, including West Nile (WNV), 34 dengue (DENV), and Zika virus (ZIKV) but had no significant effect on the replication of 35 the (-)ssRNA viruses vesicular stomatitis (VSV, Rhabdoviridae family) and Rift Valley 36 fever (RVFV, Phenuiviridae family). Despite that WNV titers in Slfn11-deficient cells were 37 almost 100-fold higher than in cells expressing this protein; they produced approximately 38 two-fold less viral particles, as determined by PCR-based quantification of virion-39 associated WNV RNA in the cell culture supernatant. These data indicated that Slfn11 40 impairs WNV fitness but does not affect other steps of the viral life cycle including entry, 41 viral RNA replication and translation, and budding. Similarly to the proposed anti-HIV-1 42 mechanism of Slfn11, this protein prevented WNV-induced down-regulation of a subset 43 of tRNAs implicated in the translation of 19% of the viral polyprotein. Importantly, we 44 provided evidence suggesting that the broad anti-viral activity of Slfn11 requires other 3 45 cellular proteins, since overexpression of Slfn11 in cells that naturally lack the 46 expression of this protein, did not impair WNV or HIV-1 infection. In summary, this study 47 4 49 AUTHOR SUMMARY 50The host targets mechanisms that viruses have evolved to optimize replication. We 51 provide evidence that the cellular protein Schlafen 11 (Slf11) impairs replication of 52 flaviviruses, including West Nile (WNV), dengue (DENV), and Zika virus (ZIKV). 53However, replication of single-stranded, negative RNA viruses was not affected. 54Specifically, Slf11 decreases the fitness of WNV potentially by preventing virus-induced 55 modifications of the host tRNA repertoire that could lead to enhanced viral protein 56 folding. Furthermore, we demonstrated that Slf11 is not the limiting factor of this novel 57 broad anti-viral pathway. 5 59 6 84HIV-1 activity of Slf13 is specific since this protein did not affect re...

Translation regulation of Japanese encephalitis virus revealed by ribosome profiling

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West Nile Virus Restriction in Mosquito and Human Cells: A Virus under Confinement

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