TRBP–Dicer interaction may enhance HIV-1 TAR RNA translation via TAR RNA processing, repressing host-cell apoptosis

Abstract

The transactivating response (TAR) RNA-binding protein (TRBP) has been identified as a double-stranded RNA (dsRNA)-binding protein, which associates with a stem-loop region known as the TAR element in human immunodeficiency virus-1 (HIV-1). However, TRBP is also known to be an enhancer of RNA silencing, interacting with Dicer, an enzyme that belongs to the RNase III family. Dicer cleaves long dsRNA into small dsRNA fragments called small interfering RNA or microRNA (miRNA) to mediate RNA silencing. During HIV-1 infection, TAR RNA-mediated translation is suppressed by the secondary structure of 5′UTR TAR RNA. However, TRBP binding to TAR RNA relieves its inhibitory action of translation and Dicer processes HIV-1 TAR RNA to generate TAR miRNA. However, whether the interaction between TRBP and Dicer is necessary for TAR RNA translation or TAR miRNA processing remains unclear. In this study, we constructed TRBP mutants that were unable to interact with Dicer by introducing mutations into amino acid residues necessary for the interaction. Furthermore, we established cell lines expressing such TRBP mutants. Then, we revealed that the TRBP-Dicer interaction is essential for both the TAR-containing RNA translation and the TAR miRNA processing in HIV-1.

MicroRNAs: Small but Key Players in Viral Infections and Immune Responses to Viral Pathogens

“…There is concern that the excision of miRNA or miRNAlike fragments could result in cleavage of the viral genome and hinder viral replication [99]. It has been suggested that the HIV encodes a transactivating response (TAR) motif that includes miRNA precursors that can be produced without cleavage of the viral genome [100,101]. However, the exact mechanism of this non-canonical pathway of miRNA production is still under investigation [100,101].…”

“…It has been suggested that the HIV encodes a transactivating response (TAR) motif that includes miRNA precursors that can be produced without cleavage of the viral genome [100,101]. However, the exact mechanism of this non-canonical pathway of miRNA production is still under investigation [100,101]. That said, v-miR-TAR has been detected in the sera of HIV-infected patients along with HIV-encoded v-miR-88 and v-miR-199 [102].…”

From Entry to Egress: Strategic Exploitation of the Cellular Processes by HIV-1

“…HIV-1 also recruits host TAR RNA-binding protein (TRBP-known to be involved in RNA silencing) at TAR elements and resolve the secondary structure for translation initiation. This year, Komori et al (2020) showed that TRBP interacts with the DICER and mediates TAR miRNA degradation, reliving the hurdle. Apart from canonical translation initiation, eukaryotes and many viruses, including HIV-1, employ a capindependent translation mechanism.…”

The interaction between RPAP3 and TRBP reveals a possible involvement of the HSP90/R2TP chaperone complex in the regulation of miRNA activity

“…The 5′-terminal TAR stem-loop structure of HIV RNAs impedes efficient translation of the viral RNAs ( 4 ) and TRBP binding to this element relieves this negative effect. Interestingly, Dicer was also recently proposed to be involved in this process ( 5 ). TRBP was additionally shown to promote HIV infection by directly or indirectly inhibiting PKR activation, which is triggered by the TAR RNA and leads to global translation inhibition ( 6 ).…”