N6-methyladenosine bimodal peak signature mediates acute and selective stress translation by specialized cytoskeletal ribosomes via a MARK4-FTO-PKR axis

Abstract

Cellular responses to stress are temporally-organized complex pathways designed to prioritize resources and adapt in order to promote repair and survival. In severe stress, the energetically demanding mRNA translation is mostly inhibited, but it is not known whether there is a universal mechanism that preserves the translation of acutely needed stress response proteins (SRPs). Here we show that the dynamic epitranscriptomic n6-methyladenosine (m6A) mRNA modification is used as an SRP mRNA marker, allowing for selective translation in microdomains consisting of specialized ribosomes (compatible with the recent discovery of ribosomal diversity), the m6A demethylase FTO, and stress related kinases (MARK4 and PKR), attached on the cytoskeleton (i.e. g tubulin). SRP mRNAs are characterized by a dual peak methylation pattern, downstream of their 3UTR segment, which hosts the eIF2a kinase PKR that inhibits their translation when they exit the nucleus. FTO, which also binds at the same site, is activated via a T6 phosphorylation by the stress kinase MARK4 and removes this dual peak methylation signature, removing the inhibitory effects of PKR, allowing the translation of SRPs. We describe a previously unrecognized, microtubule associated translation system for the translation of SRPs during the critical early stages of acute stress, when the translation of other proteins is mostly inhibited.