Terminal uridylyltransferases target RNA viruses as part of the innate immune system

Abstract

RNA viruses are a major threat to animals and plants. RNA interference (RNAi) and the interferon response provide innate antiviral defense against RNA viruses. Here, we performed a large-scale screen using Caenorhabditis elegans and its natural pathogen the Orsay virus (OrV), and we identified cde-1 as important for antiviral defense. CDE-1 is a homolog of the mammalian TUT4 and TUT7 terminal uridylyltransferases (collectively called TUT4(7)); its catalytic activity is required for its antiviral function. CDE-1 uridylates the 3' end of the OrV RNA genome and promotes its degradation in a manner independent of the RNAi pathway. Likewise, TUT4(7) enzymes uridylate influenza A virus (IAV) mRNAs in mammalian cells. Deletion of TUT4(7) leads to increased IAV mRNA and protein levels. Collectively, these data implicate 3'-terminal uridylation of viral RNAs as a conserved antiviral defense mechanism.

Innate Immune Evasion by Human Respiratory RNA Viruses

“…Recent data hint at the importance of protecting the 3′ ends of viral RNAs as well, besides the 5′ ends, as it was shown that Tut4 and Tut7, 2 cellular terminal uridylyltransferases, can add one or 2 uridines to the 3′ ends of polyadenylated influenza mRNAs, as well as RNAs of several other viruses, to target these RNAs for degradation by cellular machineries [75][76][77]. Additionally, a recent report indicated that cytosolic coronaviral mRNAs are targeted by the cellular nonsense-mediated decay pathway, a pathway that detects aberrant translation termination DOI: 10.1159/000503030 features such as premature termination codons in mRNA, resulting in the degradation of these mRNAs [78].…”

MicroRNA arm switching regulated by uridylation

“…DROSHA introduces a 39 staggered cut, liberating a small hairpin of~65 nt with a 2-nt 3 ′ overhang 40 (called pre-miRNA). Following pre-miRNA export to the cytoplasm, 41 DICER recognizes the 2-nt 3 ′ overhang on pre-miRNA using its platform 42 and PAZ domains ( Pre-miRNA with a relatively unstable 5 ′ end (e.g., mismatch, G-U, or 47 A-U pair) would be readily captured by the 5 ′ pocket (in the platform 48 domain) of DICER and the cleavage site is dictated by the distance from 49 3/51 the 5 ′ end ("5 ′ -counting rule") (Park et al, 2011;Tian et al, 2014). On 50 the other hand, pre-miRNA with a stable 5 ′ end (e.g., G-C pair) relies on 51 the interaction between its 3 ′ end and the 3 ′ pocket (in the PAZ domain) 52 of DICER and is cleaved at the site~22 nt away from its 3 ′ end 53 at both ends, which is subsequently loaded onto an Argonaute (AGO) 56 protein with the help from HSC70/HSP90 chaperone machinery (Iwasaki 57 et al, 2010; Naruse et al, 2018).…”

CDE-1 suppresses the production of risiRNA by coupling polyuridylation and degradation of 26S rRNA

“…Terminal modification is critical in biology. For example, uridylation is implicated in tumorigenesis, proliferation, stem cell maintenance, and immune defense against viruses and retrotransposons (Blahna, Jones et al, 2011, Hagan, Piskounova et al, 2009, Jones, Quinton et al, 2009, Le Pen, Jiang et al, 2018, Warkocki, Krawczyk et al, 2018, Yeo & Kim, 2018). The C. elegans genome encodes three polyuridylation polymerases (PUPs): cde-1/pup-1/cid-1 , pup-2 and pup-3 (Kwak & Wickens, 2007).…”

“…These PUPs may have distinct roles in different cellular contexts. cde-1 is involved in the inheritance of RNAi, chromosome segregation and antiviral defense (Le Pen et al, 2018, van Wolfswinkel, Claycomb et al, 2009, Xu, Feng et al, 2018). CDE-1 functions with the RNA-dependent RNA polymerase (RdRP) EGO-1 and the Argonaute CSR-1 in the germline to affect chromosome segregation (Claycomb, Batista et al, 2009).…”