Uncovering Flavivirus Host Dependency Factors through a Genome-Wide Gain-of-Function Screen

Petrova, Evgeniya; Gracias, Ségolène; Beauclair, Guillaume; Tangy, Frédéric; Jouvenet, Nolwenn

doi:10.3390/v11010068

Cited by 19 publications

(23 citation statements)

References 46 publications

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“…1A). Numerous research groups have demonstrated that these RPs may be utilized by diverse viruses for efficient viral infection (25,30,(37)(38)(39)(40)(41)(42)(43)(44). Notably, the candidate protein RPL13, a member of the L13E family, is conserved in a wide range of species, including plants, yeast, and animals (45,46).…”

Section: Resultsmentioning

confidence: 99%

Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner

Han

Sun

et al. 2020

J Virol

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Internal ribosome entry site (IRES)-driven translation is a common strategy among positive-sense, single-stranded RNA viruses for bypassing the host cell requirement of a 5′ cap structure. In the current study, we identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation of foot-and-mouth disease virus (FMDV) but found that it is not essential for cellular global translation. RPL13 is also a determinant for translation and infection of Seneca Valley virus (SVV) and classical swine fever virus (CSFV), and this suggests that its function may also be conserved in unrelated IRES-containing viruses. We further showed that depletion of DEAD box helicase DDX3 disrupts binding of RPL13 to the FMDV IRES, whereas the reduction in RPL13 expression impairs the ability of DDX3 to promote IRES-driven translation directly. DDX3 cooperates with RPL13 to support the assembly of 80S ribosomes for optimal translation initiation of viral mRNA. Finally, we demonstrated that DDX3 affects the recruitment of the eukaryotic initiation factor eIF3 subunits e and j to the viral IRES. This work provides the first connection between DDX3 and eIF3e/j and recognition of the role of RPL13 in modulating viral IRES-dependent translation. This previously uncharacterized process may be involved in selective mRNA translation. IMPORTANCE Accumulating evidence has unveiled the roles of ribosomal proteins (RPs) belonging to the large 60S subunit in regulating selective translation of specific mRNAs. The translation speciﬁcity of the large-subunit RPs in this process is thought provoking, given the role they play canonically in catalyzing peptide bond formation. Here, we have identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation during FMDV infection. Our study supports a model whereby the FMDV IRESs recruit helicase DDX3 recognizing RPL13 to facilitate IRES-driven translation, with the assistance of eIF3e and eIF3j. A better understanding of these specific interactions surrounding IRES-mediated translation initiation could have important implications for the selective translation of viral mRNA and thus for the development of effective prevention of viral infection.

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Section: Resultsmentioning

confidence: 99%

Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner

Han

Sun

et al. 2020

J Virol

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“…Genome-scale CRISPR and siRNA screens and proteomic analysis of cellular proteins associated with ZIKV or DENV proteins identified numerous host factors required for viral replication (38)(39)(40)(41)(44)(45)(46). A large part of these host dependency factors are localized in the ER.…”

Section: Discussionmentioning

confidence: 99%

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Monel

Rajah

Hafirassou

et al. 2019

J Virol

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The endoplasmic reticulum (ER) is the site for Zika virus (ZIKV) replication and is central to the cytopathic effects observed in infected cells. ZIKV induces the formation of ER-derived large cytoplasmic vacuoles followed by “implosive” cell death. Little is known about the nature of the ER factors that regulate flavivirus replication. Atlastins (ATL1, -2, and -3) are dynamin-related GTPases that control the structure and the dynamics of the ER membrane. We show here that ZIKV replication is significantly decreased in the absence of ATL proteins. The appearance of infected cells is delayed, the levels of intracellular viral proteins and released virus are reduced, and the cytopathic effects are strongly impaired. We further show that ATL3 is recruited to viral replication sites and interacts with the nonstructural viral proteins NS2A and NS2B3. Thus, proteins that shape and maintain the ER tubular network ensure efficient ZIKV replication. IMPORTANCE Zika virus (ZIKV) is an emerging virus associated with Guillain-Barré syndrome, and fetal microcephaly as well as other neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We found that endoplasmic reticulum (ER)-shaping atlastin proteins (ATL1, -2, and -3), which induce ER membrane fusion, facilitate ZIKV replication. We show that ATL3 is recruited to the viral replication site and colocalize with the viral proteins NS2A and NS2B3. The results provide insights into host factors used by ZIKV to enhance its replication.

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“…The cDNA was subsequently amplified using DreamTaq DNA polymerase (ThermoFisher Scientific). The 20-µL reaction volume contained 1x of reaction mix and 10 µM of primers (forward: 5′-GCGTAAGGCTGGAAAGAGTG-3′; reverse: 5′-CTTCCTCCCTTCATCCACAA-3′) 40 . The thermocycling program was 2 min at 95 °C, 35 cycles of 30 sec at 95 °C, 30 sec at 60 °C, and 30 sec at 72 °C with a final extension step of 7 min at 72 °C.…”

Section: Methodsmentioning

confidence: 99%

Risk of arbovirus emergence via bridge vectors: case study of the sylvatic mosquito Aedes malayensis in the Nakai district, Laos

Miot

Calvez²,

Aubry

et al. 2020

Sci Rep

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Many emerging arboviruses of global public health importance, such as dengue virus (DenV) and yellow fever virus (YfV), originated in sylvatic transmission cycles involving wild animals and forest-dwelling mosquitoes. Arbovirus emergence in the human population typically results from spillover transmission via bridge vectors, which are competent mosquitoes feeding on both humans and wild animals. Another related, but less studied concern, is the risk of 'spillback' transmission from humans into novel sylvatic cycles. We colonized a sylvatic population of Aedes malayensis from a forested area of the nakai district in Laos to evaluate its potential as an arbovirus bridge vector. We found that this Ae. malayensis population was overall less competent for DenV and YfV than an urban population of Aedes aegypti. olfactometer experiments showed that our Ae. malayensis colony did not display any detectable attraction to human scent in laboratory conditions. the relatively modest vector competence for DenV and YfV, combined with a lack of detectable attraction to human odor, indicate a low potential for this sylvatic Ae. malayensis population to act as an arbovirus bridge vector. However, we caution that opportunistic blood feeding on humans by sylvatic Ae. malayensis may occasionally contribute to bridge sylvatic and human transmission cycles.

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Uncovering Flavivirus Host Dependency Factors through a Genome-Wide Gain-of-Function Screen

Cited by 19 publications

References 46 publications

Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner

Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Risk of arbovirus emergence via bridge vectors: case study of the sylvatic mosquito Aedes malayensis in the Nakai district, Laos

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