m6A depletion attenuates the macrophage type I interferon response
TL;DR
It is found that in THP1-derived and peripheral blood macrophages, m6A depletion with the METTL3 inhibitor STM2457 leads to enhanced proliferation of the human coronavirus OC43 and it is concluded that macrophages depend on m6A to support expression of interferon sensing machinery and in m6A’s absence, fail to mount as strong of a type I interferon response.
Abstract
Macrophages play an important role in coordinating the antiviral response and post-transcriptional regulation of mRNA is an important element of the inflammatory gene expression required for defense against viral pathogens. N6-methyladenosine (m6A) deposition on mRNA by METTL3 constitutes one such post-transcriptional event which facilitates a cascade of downstream regulation via RNA decay and translation. We discovered that in THP1-derived and peripheral blood macrophages, m6A depletion with the METTL3 inhibitor STM2457 leads to enhanced proliferation of the human coronavirus OC43. Using TimeLapse-seq to comprehensively measure changes in abundance, RNA decay and transcription, we find that STM2457 downregulates the interferon response far upstream by reducing expression of both the type I interferon receptor and STAT1. We conclude that macrophages depend on m6A to support expression of interferon sensing machinery and in m6A’s absence, fail to mount as strong of a type I interferon response.