Mettl3-mediated mRNA m⁶A methylation promotes dendritic cell activation.

Abstract

N6-methyladenosine (m⁶A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m⁶A modification is involved in innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated mRNA m⁶A methylation promotes dendritic cell (DC) activation and function. Specific depletion of Mettl3 in DC resulted in impaired phenotypic and functional maturation of DC, with decreased expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12, and reduced ability to stimulate T cell responses both in vitro and in vivo. Mechanistically, Mettl3-mediated m⁶A of CD40, CD80 and TLR4 signaling adaptor Tirap transcripts enhanced their translation in DC for stimulating T cell activation, and strengthening TLR4/NF-κB signaling-induced cytokine production. Our findings identify a new role for Mettl3-mediated m⁶A modification in increasing translation of certain immune transcripts for physiological promotion of DC activation and DC-based T cell response.