The m6A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay

Abstract

The role m6A modifications have increasingly been associated with diverse set of roles in modulating viruses and influencing the outcomes of viral infection. Here we report that the landscape of m6A deposition is drastically shifted during KSHV (Kaposi Sarcoma Associated herpesvirus) lytic infection for both viral and host transcripts. In line with previous reports, we also saw an overall decrease in host methylation in favor of viral mRNA along with 5' hypomethylation and 3' hypermethylation. During KSHV lytic infection, a major shift in overall mRNA abundance is driven by the viral endoribonuclease SOX, which induces the decay of greater than 70% of transcripts. Here, we reveal that Interlukin-6 (IL-6) mRNA, a well-characterized SOX-resistant transcript, is m6A modified during lytic infection. Furthermore, we show that this modification falls within the IL-6 SOX Resistance Element (SRE), an RNA element in IL-6 3' UTR that was previously shown to be sufficient for protection from SOX cleavage. We show that the presence of this m6A modification is essential to confer SOX resistance to the IL-6 mRNA. We next show that this modification recruits the m6A reader YTHDC2 and found that YTHDC2 is necessary for the escape of the IL-6 transcript. These results shed light on how the host cell has evolved to use RNA modifications to circumvent viral manipulation of RNA fate during KSHV infection.

m6A reader proteins: the executive factors in modulating viral replication and host immune response

“…The m 6 A nuclear reader DC2 was also studied in KSHVinfected cells for its function in stabilizing RNAs, since many cellular mRNAs are degraded by KSHV endoribonuclease SOX (Macveigh-Fierro et al, 2022). This study found that the IL6 mRNA was m 6 A modified in its 3′UTR during KSHV lytic infection and that removal of this m 6 A restored susceptibility to SOX-mediated degradation.…”