Identification of an N6-methyladenosine-mediated positive feedback loop that promotes Epstein–Barr virus infection

Abstract

N6-methyladenosine (m 6 A) is among the most abundant mRNA modifications, particularly in eukaryotes, and is found in mammals, plants, and even some viruses. Although essential for the regulation of many biological processes, the exact role of m 6 A modification in virus–host interaction remains largely unknown. Here, using m 6 A -immunoprecipitation and sequencing, we find that Epstein–Barr virus (EBV) infection decreases the m 6 A modification of transcriptional factor KLF4 mRNA and subsequently increases its protein level. Mechanistically, EBV immediate-early protein BZLF1 interacts with the promoter of m 6 A methyltransferase METTL3, inhibiting its expression. Subsequently, the decrease of METTL3 reduces the level of KLF4 mRNA m 6 A modification, preventing its decay by the m 6 A reader protein YTHDF2. As a result, KLF4 protein level is upregulated and, in turn, promotes EBV infection of nasopharyngeal epithelial cells. Thus, our results suggest the existence of a positive feedback loop formed between EBV and host molecules via cellular mRNA m 6 A levels, and this feedback loop acts to facilitate viral infection. This mechanism contains multiple potential targets for controlling viral infectious diseases.

Methionine Metabolism Controls the B-cell EBV Epigenome and Viral Latency

“…Since EBNA2, LP and 3 are expressed from a common C or W promoter driven transcript, we speculate that methionine metabolism also has important roles in EBNA post-transcriptional regulation, perhaps at the level of splicing. In support, methionine-derived SAM is the methyl donor for RNA methylation reactions, and RNA methylation is increasingly recognized as a key regulator of EBV-encoded mRNAs (Dai et al, 2021; Lang et al, 2019; Xia et al, 2021; Zheng et al, 2021). EBNA2 mRNAs are modified by N6-methyladenosine (m6A) marks, and knockdown of the m6A writer METTL3 decreases EBNA2 expression levels (Zheng et al, 2021).…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Two recent studies reported that the EBV infection induces changes in N 6 -methyladenosine RNA methylation of viral and host cell mRNA. These epitransciptomic changes promoted EBV infection in vitro [ 391 , 392 ]. Once more, viruses take advantages of cellular processes to favor their life cycle.…”

CircDDX17 enhances CVB3 replication by N6-methyladenosine regulation through miR-1248/NOTCH2 targeting

“…In previous researches, m6A methylation negatively regulates the production of hepatitis C virus and avivirus Zika [11]. In other research, METTL3 inhibits Enterovirus 71 by autophagy regulation [12], decreases syndrome coronavirus clade 2 viral load and viral gene expression in host cells [13], and promotes Epstein-Barr virus infection of nasopharyngeal epithelial cells [14].…”