Stem-loop induced ribosome queuing in the uORF2/ATF4overlap fine-tunes stress-induced humanATF4translational control

Author:

Smirnova Anna M.,Hronová Vladislava,Mohammad Mahabub Pasha,Herrmannová Anna,Gunišová Stanislava,Petráčková Denisa,Halada Petr,Coufal Štěpán,Świrski Michał,Rendleman Justin,Jendruchová Kristína,Hatzoglou Maria,Beznosková Petra,Vogel Christine,Valášek Leoš ShivayaORCID

Abstract

SUMMARYATF4 is a master transcriptional regulator of the integrated stress response leading cells towards adaptation or death. ATF4’s induction under stress was thought to be mostly due to delayed translation reinitiation, where the reinitiation-permissive uORF1 plays a key role. Accumulating evidence challenging this mechanism as the sole source ofATF4translation control prompted us to investigate additional regulatory routes. We identified a highly conserved stem-loop in the uORF2/ATF4overlap, immediately preceded by a near-cognate CUG, which introduces another layer of regulation in the form of ribosome queuing. These elements explain how the inhibitory uORF2 can be translated under stress, confirming prior observations, but contradicting the original regulatory model. We also identified two highly conserved, potentially modified adenines performing antagonistic roles. Finally, we demonstrate that the canonical ATF4 translation start site is consistently leaky-scanned. Thus,ATF4’stranslational control is more complex than originally described underpinning its key role in diverse biological processes.

Publisher

Cold Spring Harbor Laboratory

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