Abstract

   Double-stranded RNA (dsRNA) is a virus-encoded signature capable of
   triggering intracellular Rig-like receptors (RLR) to activate antiviral
   signaling, but whether intercellular dsRNA structural reshaping
   mediated by the N^6-methyladenosine (m^6A) modification modulates this
   process remains largely unknown. Here, we show that, in response to
   infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m^6A
   methyltransferase METTL3 translocates into the cytoplasm to increase
   m^6A modification on virus-derived transcripts and decrease viral dsRNA
   formation, thereby reducing virus-sensing efficacy by RLRs such as
   RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the
   genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced
   type I IFN expression and accelerates VSV clearance. Our findings thus
   implicate METTL3-mediated m^6A RNA modification on viral RNAs as a
   negative regulator for innate sensing pathways of dsRNA, and also hint
   METTL3 as a potential therapeutic target for the modulation of
   anti-viral immunity.

   Subject terms: Epigenetics, Antimicrobial responses, Monocytes and
   macrophages, RIG-I-like receptors
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   N^6-methyladenosine (m^6A) RNA modification regulates RNA metabolism,
   and has been implicated in immune regulation. Here, the authors show
   that the m^6A methyltransferase, METTL3, translocates into the
   cytoplasm to increase viral RNA m^6A modification, decreases viral ds
   RNA content, and thereby dampens the RIG/MDA5-induced anti-viral
   immunity.

Introduction

   Pathogenic RNA viruses are considered as the primary etiological agents
   of human emerging pathogens and represent a challenge for global
   disease control. Therefore, it is critical to know the mechanism and
   interaction between RNA virus and host innate immunity. The innate
   immune system, highly conserved among plants and animals, recognizes
   the invading pathogens through pattern recognition receptors (PRRs) to
   trigger an effective immune response for defending the pathogens^[58]1.
   The virus-encoded molecular signatures, including cytosolic
   double-stranded RNA (dsRNA) and other distinct RNA species, trigger
   intracellular nucleic acid sensors, including retinoic acid-induced
   gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5),
   to recognize these “non-self” RNAs and activate antiviral
   signaling^[59]2–[60]4. Despite RIG-I and MDA5 show different
   preferences for sensing of 5′ ppp/ short dsRNA and long dsRNA,