A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis

Viruses express several classes of non-coding RNAs1; the functions and mechanisms by which most of these act are unknown. Herpesvirus saimiri, a gamma-herpesvirus that establishes latency in the T cells of New World primates and has the ability to cause aggressive leukaemias and lymphomas in non-natural hosts(2), expresses seven small nuclear uracil-rich non-coding RNAs (called HSURs) in latently infected cells(3-5). These HSURs associate with Sm proteins, and share biogenesis and structural features with cellular Sm-class small nuclear RNAs4,6. One of these HSURs (HSUR2) base-pairs with two host cellular microRNAs (miR-142-3p and miR-16(7)) but does not affect their abundance or activity, which suggests that its interactions with them perform alternative functions. Here we show that HSUR2 also base-pairs with mRNAs in infected cells. We combined in vivo psoralen-mediated RNA-RNA crosslinking and high-throughput sequencing to identify the mRNAs targeted by HSUR2, which include mRNAs that encode retinoblastoma and factors involved in p53 signalling and apoptosis. We show that HSUR2 represses the expression of target mRNAs and that base pairing between HSUR2 and miR-142-3p and miR-16 is essential for this repression, suggesting that HSUR2 recruits these two cellular microRNAs to its target mRNAs. Furthermore, we show that HSUR2 uses this mechanism to inhibit apoptosis. Our results uncover a role for this viral Sm-class RNA as a microRNA adaptor in the regulation of gene expression that follows precursor mRNA processing.