The m ⁶ A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay

Abstract

The role of N6-methyladenosine (m6A) modifications has increasingly been associated with a 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 Kaposi’s sarcoma–associated herpesvirus (KSHV) 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 messenger RNA (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, an RNA element in the IL-6 3′ untranslated region (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.

Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

“…Interestingly, this effect can still be observed when accounting for the nucleotide composition of the genomes and hence taking into account the high GC content of some alphaherpesviruses, such as PRV and HSV-1 ( Figure S5 ). Of additional interest, the latter analysis shows a significant enrichment of the DRACH motif in the genomes of gammaherpesviruses, in line with the notion that viral transcripts of different members of this herpesvirus subfamily are m6A methylated, which is thought to be important for different aspects of the biology of these viruses ( Tan et al, 2017 ; Ye et al, 2017 ; Hesser et al, 2018 ; Baquero-Perez et al, 2019 ; Lang et al, 2019 ; Dai et al, 2021 ; Tang et al, 2021 ; Xia et al, 2021 ; Zheng et al, 2021 ; Macveigh-Fierro et al, 2022 ).…”

METTL3 inhibits autoreactive Th17 cell responses in experimental autoimmune uveitis via stabilizing ASH1L mRNA

“…m6A readers, such as YTH-domain family proteins, have been proved to modulate gene expression via recognizing m6A-transcripts, and both the YTHDC1 and YTHDC2 were associated with methylated mRNA stability. 39,40 Via bioinformatics analysis, we identified that YTHDC2 interacted with ASH1L mRNA, and that the binding site of YTHDC2 overlapped with the m6A site of ASH1L mRNA, suggesting that YTHDC2 might participate in the regulation of ASH1L expression. By recognizing the m6A site, YTHDC2 sustained CYLD mRNA stability in lung cancer cells 41 and protected IL-6 mRNA from SOX degradation during KSHV lytic infection.…”

YTHDC2 Promotes Malignant Phenotypes of Breast Cancer Cells

“…In other studies, YTHDC2 has been shown to regulate the translation of some genes, such as IGF1R and HCV, by eliminating the secondary structure of its mRNA [4,11,14]. On the other hand, some studies reported that YTHDC2 is also involved in the stability of m 6 A-modified mRNAs, such as meiosis-related genes and interleukin-6 gene [26,27]. m 6 A modification has been found in SOX2, c-MYC, and NANOG mRNAs and is thought to regulate the stabilization/destabilization and translation of them [28][29][30].…”