Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720308767 |
| _version_ | 1818693164316229632 |
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| author | Xiaoqiang Zhu He Zhang Joshua T. Mendell |
| author_facet | Xiaoqiang Zhu He Zhang Joshua T. Mendell |
| author_sort | Xiaoqiang Zhu |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-17T13:09:20Z |
| format | Article |
| id | doaj.art-a2cdb3f374274158b2c074188f94c6e2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T13:09:20Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-a2cdb3f374274158b2c074188f94c6e22022-12-21T21:47:10ZengElsevierCell Reports2211-12472020-07-01322107895Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated DecayXiaoqiang Zhu0He Zhang1Joshua T. Mendell2Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USAQuantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720308767nonsense-mediated decaypost-transcriptional regulation3' untranslated region3' UTRABCE1iron-sulfur cluster |
| spellingShingle | Xiaoqiang Zhu He Zhang Joshua T. Mendell Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay Cell Reports nonsense-mediated decay post-transcriptional regulation 3' untranslated region 3' UTR ABCE1 iron-sulfur cluster |
| title | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay |
| title_full | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay |
| title_fullStr | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay |
| title_full_unstemmed | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay |
| title_short | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3ʹ UTR-Directed Regulation and Nonsense-Mediated Decay |
| title_sort | ribosome recycling by abce1 links lysosomal function and iron homeostasis to 3 utr directed regulation and nonsense mediated decay |
| topic | nonsense-mediated decay post-transcriptional regulation 3' untranslated region 3' UTR ABCE1 iron-sulfur cluster |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720308767 |
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