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bioRxiv · 10.64898/2026.08.14.744930

m6A depletion attenuates the macrophage type I interferon response

Courvan, E. M. C.·Hecht, C. J. S.·Longshore-Neate, F.·Vasconcelos, L. M.·Parker, R.
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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 m6As absence, fail to mount as strong of a type I interferon response.

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Courvan, E. M. C., Hecht, C. J. S., Longshore-Neate, F., Vasconcelos, L. M., Parker, R.. 2026-08-20. m6A depletion attenuates the macrophage type I interferon response. https://doi.org/10.64898/2026.08.14.744930

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