Noncanonical MicroRNA (miRNA) Biogenesis Gives Rise to Retroviral Mimics of Lymphoproliferative and Immunosuppressive Host miRNAs

Abstract

MicroRNAs (miRNAs) play regulatory roles in diverse processes in both eukaryotic hosts and their viruses, yet fundamental questions remain about which viruses code for miRNAs and the functions that they serve. Simian foamy viruses (SFVs) of Old World monkeys and apes can zoonotically infect humans and, by ill-defined mechanisms, take up lifelong infections in their hosts. Here, we report that SFVs encode multiple miRNAs via a noncanonical mode of biogenesis. The primary SFV miRNA transcripts (pri-miRNAs) are transcribed by RNA polymerase III (RNAP III) and take multiple forms, including some that are cleaved by Drosha. However, these miRNAs are generated in a context-dependent fashion, as longer RNAP II transcripts spanning this region are resistant to Drosha cleavage. This suggests that the virus may avoid any fitness penalty that could be associated with viral genome/transcript cleavage. Two SFV miRNAs share sequence similarity and functionality with notable host miRNAs, the lymphoproliferative miRNA miR-155 and the innate immunity suppressor miR-132. These results have important implications regarding foamy virus biology, viral miRNAs, and the development of retroviral-based vectors.

RETRACTED: Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

“…1A). As expected, miR-132, which has previously been shown to inhibit IFN signaling (35,36) scored in our assay by reducing the IFN-induced transcription of the firefly-Luc reporter by 35%. Additionally, three herpesviral miRNAs consistently scored as having a ≥25% reduction (Fig.…”

“…S1). We chose to screen for miRNA-mediated inhibition of IFN as a potential widespread activity of viruses for two reasons: (i) proteins that hinder the IFN response are nearly universal among mammalian viruses, and (ii) we have already demonstrated that the unrelated viruses, Torque teno virus tth8 (TTV-tth8) and Simian Foamy virus of African green monkey (SFVagm) encode miRNAs that inhibit type I IFN signaling (34,35). Thus, we conducted a screen to identify those human viral miRNAs that block IFNmediated signaling.…”

Virus Meets Host MicroRNA: the Destroyer, the Booster, the Hijacker

“…Similarly, one viral miRNA produced by B-lymphotropic BLV, BLV-miR-B4, shares its seed sequence with host B-cell tumorigenic miR-29a (55). All of these viral miRNA mimics target the same set of genes as their host counterparts (54,55).…”

“…SFV of African green monkeys (SFVagm) produces at least 6 mature miRNAs from its long terminal repeat (LTR) regions by RNA polymerase III transcription (54). Two of these viral miRNAsSFVagm-miR-S4-3p and SFVagm-miR-S6-3p-exhibit seed sequence homology with host lymphoproliferative miR-155 and immunosuppressive miR-132, respectively (54). Similarly, one viral miRNA produced by B-lymphotropic BLV, BLV-miR-B4, shares its seed sequence with host B-cell tumorigenic miR-29a (55).…”

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

“…However, a few viruses generate miRNAs using unconventional mechanisms and proteins, such as RNAP III, tRNase Z, and the integrator complex (Pfeffer et al 2005;Bogerd et al 2010;Diebel et al 2010;Cazalla et al 2011;Kincaid et al , 2014Burke et al 2014;Diebel et al 2014;Feldman et al 2014). Previous work from our laboratory and others has demonstrated that the miRNAs derived from the 5 ′ end of 5 ′ triphosphorylated miRNA precursors expressed by bovine leukemia virus (BLV) and human adenovirus (AdV) predominantly contain a 5 ′ monophosphate (Xu et al 2009;Burke et al 2014).…”