C19ORF66 broadly escapes viral-induced endonuclease cleavage and restricts Kaposi’s Sarcoma Associated Herpesvirus (KSHV)

William Rodriguez; Aman Srivastav; Mandy Muller

(1-5). This process, known as "host shutoff", allows viruses to rapidly restrict gene expression in 30 order to dampen immune responses and provide access to the host's resources for viral 31 replication (2,6,7). One well-studied viral endonuclease is the SOX protein encoded by Kaposi's 32 sarcoma-associated herpesvirus (KSHV). SOX is conserved throughout the herpesvirus family, 33 but only gammaherpesviral SOX homologs display ribonuclease activity in cells (8) (9) (10) and 34 studies indicate that SOX activity is important for the in-vivo viral lifecycle (11,12). Although SOX 35 targets a degenerate RNA motif present on most mRNA (13-15), multiple studies have shown 36 that some transcripts robustly escape SOX-induced decay (16-21). Studying these 'escapees' in 37 aggregate is complicated, however, by the fact that multiple mechanisms can promote apparent 38 escape. These include lack of a targeting motif, indirect transcriptional effects, and active 39 evasion of ribonucleolytic cleavage (16,20-24). This latter phenotype, termed "dominant 40 escape", is particularly notable as it involves a specific RNA element whose presence in the 3' 41 UTR of an mRNA protects against SOX cleavage, regardless of whether the RNA contains a 42 targeting motif (19-21). This protective RNA element was termed SRE (for SOX Resistance 43 Element), but we recently showed that the SRE is also effective against a broad range of viral 44 endonucleases. Perhaps more surprisingly, the SRE is unable to restrict endonucleolytic 45 cleavage originating from a cellular endonuclease, making it the first identified viral-specific 46 ribonuclease escape element (19) . We showed that this broad-acting RNA element is not 47