Biology subjects

Gaete-Argel, A.

Publications and source records attributed to Gaete-Argel, A..

3 recordsLinked to original sources

bioRxiv2026

DEAD-box RNA helicase DDX3X maintains the homeostasis of the Zika virus translation-replication cycle

DDX3X is a cellular DEAD-box ATP-dependent RNA helicase known to play pivotal roles during the replication cycle of different viruses including some flaviviruses. Whether DDX3X plays a role during replication of Zika virus (ZIKV), a mosquito-borne flavivirus with a broad tissue tropism, has not been explored in detail. Here, we show that DDX3X is required for efficient ZIKV replication in a human microglia cell line but no other cell lines. Mechanistically, we provide evidence showing that DDX3X is recruited to the viral replication compartments where it binds to the 5UTR of the ZIKV RNA and promotes viral protein synthesis in an ATP-dependent manner. We also show that DDX3X binds to the viral RNA-dependent RNA polymerase NS5 and interferes with viral RNA synthesis in an ATP-independent manner. Such an effect was not observed during replication of Dengue 2 virus in human microglia, revealing specific roles for DDX3X in the regulation of the translation-replication cycle of ZIKV in human microglia. IMPORTANCEZika virus emerged as a major threat to humans due to its pandemic potential and its association with birth defects and neurological complications. The lack of available vaccines or specific treatments makes the understanding of Zika virus-host interactions a priority. Here, we demonstrate a mechanism by which DDX3X, a cellular ATP-dependent RNA helicase, promotes Zika virus replication by regulating the translation-replication cycle in a human microglia cell line. Considering the threat of this virus to the human population and the wide range of RNA viruses that usurp this host protein to accomplish the replication cycle, DDX3X continuously rises as a potential and valuable target for pharmacological intervention.

microbiology↗

bioRxiv2019

CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev

Translation initiation of the human immunodeficiency virus type-1 (HIV-1) unspliced mRNA has been shown to occur through cap-dependent and IRES-driven mechanisms. Previous studies suggested that the nuclear cap-binding complex (CBC) rather than eIF4E drives cap-dependent translation of the unspliced mRNA and we have recently reported that the CBC subunit CBP80 supports the function of the viral protein Rev during nuclear export and translation of this viral transcript. Ribosome recruitment during CBC-dependent translation of cellular mRNAs relies on the activity CBP80/20 translation initiation factor (CTIF), which bridges CBP80 and the 40S ribosomal subunit through interactions with eIF3g. Here, we report that CTIF restricts HIV-1 replication by interfering with Gag synthesis from the unspliced mRNA. Our results indicate that CTIF associates with Rev through its N-terminal domain and is recruited onto the unspliced mRNA ribonucleoprotein complex in order to block translation. We also demonstrate that CTIF induces the cytoplasmic accumulation of Rev impeding the association of the viral protein with CBP80. We finally show that CTIF restricts HIV-2 but not MLV Gag synthesis indicating an inhibitory mechanism conserved in Rev-expressing human lentiviruses.

microbiology↗

bioRxiv2018

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with Rev to promote Gag synthesis. Interestingly, molecular docking analyses revealed the assembly of a Rev-CBP80-eIF4AI complex that is organized around the Rev response element (RRE). Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.

molecular biology↗