@article{34e1c26ab3e74e3a8fc1104ca9e01210,
title = "Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay",
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 3ʹ 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 3ʹ 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 3ʹ 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 3ʹ UTR-directed regulation to lysosomal dysfunction, iron deficiency, and oxidative stress.",
keywords = "3' UTR, 3' untranslated region, ABCE1, iron homeostasis, iron-sulfur cluster, lysosome, nonsense-mediated decay, post-transcriptional regulation",
author = "Xiaoqiang Zhu and He Zhang and Mendell, {Joshua T.}",
note = "Funding Information: We thank David Root, John Doench, Feng Zhang, Didier Trono, Xiaojun Lian, and Nancy L. Craig for plasmids; Vanessa Schmid, Rachel Bruce, and Caitlin Eaton in the McDermott Center Next Generation Sequencing Core for assistance with high-throughput sequencing; Angie Mobley and the UT Southwestern Flow Cytometry Core facility for FACS; and Michael Buszczak, Kathryn O'Donnell, and members of the Mendell laboratory for helpful comments on the manuscript. This work was supported by grants from CPRIT (RP150596 to the UTSW Bioinformatics Core Facility), the NIH (R35CA197311, P30CA142543, and P50CA196516 to J.T.M.), and the Welch Foundation (I-1961-20180324 to J.T.M.). J.T.M. is an Investigator of the Howard Hughes Medical Institute. X.Z. and J.T.M. designed the experiments and interpreted the results. X.Z. performed all experiments. H.Z. analyzed ribosome profiling data and RNA-seq data. X.Z. and J.T.M. wrote the manuscript. J.T.M. is a member of the scientific advisory board of Ribometrix. Funding Information: We thank David Root, John Doench, Feng Zhang, Didier Trono, Xiaojun Lian, and Nancy L. Craig for plasmids; Vanessa Schmid, Rachel Bruce, and Caitlin Eaton in the McDermott Center Next Generation Sequencing Core for assistance with high-throughput sequencing; Angie Mobley and the UT Southwestern Flow Cytometry Core facility for FACS; and Michael Buszczak, Kathryn O{\textquoteright}Donnell, and members of the Mendell laboratory for helpful comments on the manuscript. This work was supported by grants from CPRIT ( RP150596 to the UTSW Bioinformatics Core Facility), the NIH ( R35CA197311 , P30CA142543 , and P50CA196516 to J.T.M.), and the Welch Foundation ( I-1961-20180324 to J.T.M.). J.T.M. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jul,
day = "14",
doi = "10.1016/j.celrep.2020.107895",
language = "English (US)",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}