Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3' UTR-Directed Regulation and Nonsense-Mediated Decay.

Cell Reports
Xiaoqiang ZhuJoshua T Mendell

Abstract

Nonsense-mediated decay (NMD) is a pathway that degrades mRNAs containing premature termination codons. Here we describe a genome-wide screen for NMD factors that uncovers an unexpected mechanism that broadly governs 3' untranslated region (UTR)-directed regulation. The screen reveals that NMD requires lysosomal acidification, which allows transferrin-mediated iron uptake, which, in turn, is necessary for iron-sulfur (Fe-S) cluster biogenesis. This pathway maintains the activity of the Fe-S cluster-containing ribosome recycling factor ABCE1, whose impaired function results in movement of ribosomes into 3' UTRs, where they displace exon junction complexes, abrogating NMD. Importantly, these effects extend beyond NMD substrates, with ABCE1 activity required to maintain the accessibility of 3' UTRs to diverse regulators, including microRNAs and RNA binding proteins. Because of the sensitivity of the Fe-S cluster of ABCE1 to iron availability and reactive oxygen species, these findings reveal an unanticipated vulnerability of 3' UTR-directed regulation to lysosomal dysfunction, iron deficiency, and oxidative stress.

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Citations

Feb 13, 2021·Metabolites·Joohwan Kim, Gina Lee
May 6, 2021·Wiley Interdisciplinary Reviews. RNA·Christelle MorrisEmiliano P Ricci
May 12, 2021·Cellular Signalling·Lilas AlboushiSeyed Mehdi Jafarnejad
Jun 3, 2021·Microorganisms·Antonia María RomeroSergi Puig
Mar 31, 2021·Journal of Molecular Cell Biology·Paul Jongseo LeeJunjie U Guo
Oct 15, 2021·Nature Communications·Yu H SunXin Zhiguo Li
Oct 20, 2021·PLoS Genetics·Boris ZinshteynRachel Green

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Datasets Mentioned

BETA
GSE144165

Methods Mentioned

BETA
fluorescence-activated cell sorting
FACS
flow cytometry
immunoprecipitation
RIP
RNA-seq
gene knockout
dissection
PCR
transfection

Software Mentioned

NEBuilder
STAR
Bowtie
edgeR
featureCounts
MAGeCK
DAVID

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