Schlafen 11 Restricts Flavivirus Replication.
Federico Valdez,Julienne Salvador,Pedro M. Palermo,Jonathon E. Mohl,Kathryn A. Hanley,Douglas M. Watts,Manuel Llano +6 more
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TLDR
This study demonstrates that Slfn11 restricts flavivirus replication by impairing viral infectivity and prevents WNV-induced downregulation of a subset of tRNAs implicated in the translation of 11.8% of the viral polyprotein.Abstract:
Schlafen 11 (Slfn11) is an interferon-stimulated gene that controls the synthesis of proteins by regulating tRNA abundance. Likely through this mechanism, Slfn11 has previously been shown to impair human immunodeficiency virus type 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 virus (WNV), dengue virus (DENV), and Zika virus (ZIKV), but had no significant effect on the replication of the (−)ssRNA viruses vesicular stomatitis virus (VSV) (Rhabdoviridae family) and Rift Valley fever virus (RVFV) (Phenuiviridae family). Quantification of the ratio of genome-containing viral particles to PFU indicated that Slfn11 impairs WNV infectivity. Intriguingly, Slfn11 prevented WNV-induced downregulation 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. IMPORTANCE We provide evidence that the cellular protein Schlafen 11 (Slfn11) impairs replication of flaviviruses, including West Nile virus (WNV), dengue virus (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 demonstrate that Slfn11 is not the limiting factor of this novel broad antiviral pathway.read more
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Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways.
Candice Mazewski,Ricardo E Perez,Eleanor N. Fish,Leonidas C. Platanias,Leonidas C. Platanias +4 more
TL;DR: This review summarizes signaling cascades of type I IFNs and discusses recent developments in the field, specifically as they relate to the biological and clinical implications of engagement of both canonical and non-canonical pathways.
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Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections
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Emerging Roles of tRNAs in RNA Virus Infections.
Alexandre Nunes,Diana R. Ribeiro,Mariana Groke Marques,Manuel A. S. Santos,Daniela Ribeiro,Ana R. Soares +5 more
TL;DR: This work comprehensively discusses how RNA viruses exploit distinct aspects of the host tRNA biology for their benefit and proposes that host t RNA-related pathways and mechanisms represent promising cellular targets for the development of novel antiviral strategies.
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Comparative proteomics identifies Schlafen 5 (SLFN5) as a herpes simplex virus restriction factor that suppresses viral transcription.
Eui Tae Kim,Eui Tae Kim,Eui Tae Kim,Joseph M Dybas,Joseph M Dybas,Katarzyna Kulej,Katarzyna Kulej,Emigdio D. Reyes,Emigdio D. Reyes,Alexander M. Price,Alexander M. Price,Lisa N. Akhtar,Lisa N. Akhtar,Ann Orr,Benjamin A. Garcia,Chris Boutell,Matthew D. Weitzman,Matthew D. Weitzman +17 more
TL;DR: In this article, the authors identified the cellular protein Schlafen family member 5 (SLFN5) as an ICP0 target that binds vDNA during HSV-1 ΔICP0 infection.
Journal ArticleDOI
SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243.
Yasuhisa Murai,Ukhyun Jo,Junko Murai,Lisa M. Miller Jenkins,Shar-yin N. Huang,Sirisha Chakka,Lu Chen,Ken Cheng,Shinsaku Fukuda,Naoko Takebe,Yves Pommier +10 more
TL;DR: In this article, the authors conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines and found that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN-11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR.
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