N 6 -Methyladenosine Guides mRNA Alternative Translation during Integrated Stress Response

The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2α. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains in...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cell 2018-02, Vol.69 (4), p.636
Main Authors: Zhou, Jun, Wan, Ji, Shu, Xin Erica, Mao, Yuanhui, Liu, Xiao-Min, Yuan, Xin, Zhang, Xingqian, Hess, Martin E, Brüning, Jens C, Qian, Shu-Bing
Format: Article
Language:English
Subjects:
5' Untranslated Regions
Adenosine - analogs & derivatives
Adenosine - pharmacology
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - physiology
Animals
Cells, Cultured
Codon, Initiator
Eukaryotic Initiation Factor-2 - genetics
Eukaryotic Initiation Factor-2 - metabolism
Fibroblasts
Gene Expression Regulation
HEK293 Cells
Humans
Mice
Mice, Transgenic
Peptide Chain Initiation, Translational
Phosphorylation
Ribosomes - physiology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Stress, Physiological
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2α. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains incompletely understood. Here we report that, in response to amino acid starvation, the reinitiation of ATF4 is not only governed by the eIF2α signaling pathway, but is also subjected to regulation by mRNA methylation in the form of N -methyladenosine (m A). While depleting m A demethylases represses ATF4 reinitiation, knocking down m A methyltransferases promotes ATF4 translation. We demonstrate that m A in the 5' UTR controls ribosome scanning and subsequent start codon selection. Global profiling of initiating ribosomes reveals widespread alternative translation events influenced by dynamic mRNA methylation. Consistently, Fto transgenic mice manifest enhanced ATF4 expression, highlighting the critical role of m A in translational regulation of ISR at cellular and organismal levels.
ISSN:1097-4164
DOI:10.1016/j.molcel.2018.01.019