Novel roles for Sm-class RNAs in the regulation of gene expression

Abstract

Viruses masterfully regulate host gene expression during infection. Many do so, in part, by expressing non-coding RNAs. Recent work has shown that HSUR 2, a viral non-coding RNA expressed by the oncogenic Herpesvirus saimiri, regulates mRNA expression through a novel mechanism. HSUR 2 base pairs with both target mRNAs and host miRNAs in infected cells. This results in HSUR 2-dependent recruitment of host miRNAs and associated Ago proteins to target mRNAs, and the subsequent destabilization of target mRNAs. Using this mechanism, this virus regulates key cellular pathways during viral infection. Here I discuss the evolution of our thinking about HSUR function and explore the implications of recent findings in relation to the current views on the functions of interactions between miRNAs and other classes of non-coding RNAs, the potential advantages of this mechanism of regulation of gene expression, and the evolutionary origin of HSUR 2.

How Complementary Targets Expose the microRNA 3′ End for Tailing and Trimming during Target-Directed microRNA Degradation

“…Calculations of the start, length, and hybridization energy (kcal/mol) of the two paired and one unpaired regions in miRNA−TDMD target interactions. Start denotes nucleotides from the miRNA 5 0 end (Ameres et al 2010;Baccarini et al 2011;Libri et al 2012;Marcinowski et al 2012;Lee et al 2013;Bitetti et al 2018;Cazalla 2018;Ghini et al 2018;Kleaveland et al 2018;Sheu-Gruttadauria and Pawlica et al 2019).…”

“…Despite this protection, miRNA stability varies greatly (Duffy et al 2015;Marzi et al 2016), and miRNA levels are tightly regulated (e.g., during development or the cell cycle [Monticelli et al 2005;Rissland et al 2011]). But the mechanisms of miRNA regulation are not well-understood and only two miRNA decay pathways have been described: Tudor SN-mediated miRNA decay (TumiD) (Elbarbary et al 2017) and target-directed miRNA degradation (TDMD) (Ameres et al 2010;Baccarini et al 2011;Libri et al 2012;Marcinowski et al 2012;Lee et al 2013;Bitetti et al 2018;Cazalla 2018;Ghini et al 2018;Kleaveland et al 2018). TDMD is the subject of this review.…”

“…Targets that are able to selectively induce miRNA decay, known as TDMD targets, represent various RNA classes, including ncRNAs-HSUR1 (small nuclear RNA from herpesvirus saimiri), UL144-145 (intergenic region from human cytomegalovirus), and Cyrano (cellular long ncRNA)-as well as mRNAs: m169 (from murine cytomegalovirus), NREP, and Serpine1 (Table 1; Libri et al 2012;Marcinowski et al 2012;Lee et al 2013;Bitetti et al 2018;Cazalla 2018;Ghini et al 2018;Kleaveland et al 2018). These RNAs vary not only in class and origin, but also seem to have flexible requirements for base-pairing with miRNAs to induce TDMD.…”

Idiosyncrasies of Viral Noncoding RNAs Provide Insights into Host Cell Biology

“…In the presence of HSUR2, additional downregulation of mRNAs encoding proteins involved in cell cycle regulation (RB1), apoptosis (FAS) and the immune response (JAK1) are observed: these processes are relevant to viral maintenance during latency. It is unclear how HSUR2 targets multiple mRNAs; however, unpublished evidence suggests that different segments of HSUR2 base pair with different mRNA targets ((72), Demian Cazalla, personal communication).…”