LGP2 virus sensor regulates gene expression network mediated by TRBP-bound microRNAs

Abstract

Here we show that laboratory of genetics and physiology 2 (LGP2) virus sensor protein regulates gene expression network of endogenous genes mediated by TAR-RNA binding protein (TRBP)-bound microRNAs (miRNAs). TRBP is an enhancer of RNA silencing, and functions to recruit precursor-miRNAs (pre-miRNAs) to Dicer that processes pre-miRNA into mature miRNA. Viral infection activates the antiviral innate immune response in mammalian cells. Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, melanoma-differentiation-associated gene 5 (MDA5), and LGP2, function as cytoplasmic virus sensor proteins during viral infection. RIG-I and MDA5 can distinguish between different types of RNA viruses to produce antiviral cytokines, including type I interferon. However, the role of LGP2 is controversial. We found that LGP2 bound to the double-stranded RNA binding sites of TRBP, resulting in inhibition of pre-miRNA binding and recruitment by TRBP. Furthermore, although it is unclear whether TRBP binds to specific pre-miRNA, we found that TRBP bound to particular pre-miRNAs with common structural characteristics. Thus, LGP2 represses specific miRNA activities by interacting with TRBP, resulting in selective regulation of target genes. Our findings show that a novel function of LGP2 is to modulate RNA silencing, indicating the crosstalk between RNA silencing and RLR signaling in mammalian cells.

Slicing and dicing viruses: antiviral RNA interference in mammals

“…A subsequent study showed that the IFN system actively inhibits dsRNAi at least in part through induction of LGP2, which binds Dicer and inhibits processing of long dsRNA into siRNAs (Van der Veen et al, ) (Fig ). In that study (Van der Veen et al, ), LGP binding to Dicer did not impact the biogenesis of two household miRNAs although LGP2 has also been reported to interact with the Dicer co‐factor TRBP (HIV TAR RNA‐binding protein) and inhibit the processing of a subset of TRBP‐bound miRNAs (Komuro et al, ; Takahashi et al, ). Whether LGP2 additionally inhibits dsRNAi via TRBP remains to be addressed.…”

Double-Stranded RNA Sensors and Modulators in Innate Immunity

“…LGP2 inhibits Dicer-dependent processing of pre-microRNA (miRNA) and long dsRNA, thereby suppressing biogenesis of miRNA and siRNA, respectively (65,66). These observations together suggest that RLRs have multiple functions in antiviral immunity and host dsRNA biology beyond simply activating the antiviral signaling pathway.…”

“…On the other hand, it could also suppress dsRNAdependent antiviral immunity by eliminating dsRNA ligands for RLR, PKR, and OASes. Multiple lines of evidence have suggested that RNAi and the mammalian antiviral signaling pathways are mutually inhibitory (65,66,162). Interferon signaling blocks RISC by ADPribosylation, while several interferon-stimulated genes (ISGs) were found to be targeted by RISC (162).…”

“…LGP2, a CARD-less RLR and an ISG, was also found to inhibit Dicerdependent processing of pre-miRNA and long dsRNA, thereby suppressing miRNA/siRNA biogenesis (65,66).…”

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

“…Single-molecule fluorescence techniques revealed that TRBP scans on dsRNA by an independent movement of two dsRBDs, dsRBD1 and dsRBD2, in which the diffusion distance is determined by the length of a linker domain that connects these two dsRBDs (Wang et al, 2015;Koh et al, 2016). Such a diffusion process functions as the dsRNA scanning mode of TRBP to stall off a physical barrier or bulky secondary structures (Koh et al, 2016), and TRBP recognizes dsRNA substrate with high affinity (Takahashi et al, 2013) discriminating specific structural characteristics (Takahashi et al, 2018) regardless of the end structure of the RNA. Then, TRBP positions the 3′-end of dsRNA onto the PAZ domain of Dicer to verify the authenticity of the substrate (Fareh et al, 2016).…”