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

Xiaoqiang Zhu, He Zhang, Joshua T. Mendell

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number107895
JournalCell Reports
Volume32
Issue number2
DOIs
StatePublished - Jul 14 2020

Keywords

  • 3' UTR
  • 3' untranslated region
  • ABCE1
  • iron homeostasis
  • iron-sulfur cluster
  • lysosome
  • nonsense-mediated decay
  • post-transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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