Splicing-accessible coding 3′UTRs control protein stability and interaction networks
Abstract Background 3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3′UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-07-01
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| Series: | Genome Biology |
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| Online Access: | http://link.springer.com/article/10.1186/s13059-020-02102-3 |
| _version_ | 1818043251533283328 |
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| author | Marco Preussner Qingsong Gao Eliot Morrison Olga Herdt Florian Finkernagel Michael Schumann Eberhard Krause Christian Freund Wei Chen Florian Heyd |
| author_facet | Marco Preussner Qingsong Gao Eliot Morrison Olga Herdt Florian Finkernagel Michael Schumann Eberhard Krause Christian Freund Wei Chen Florian Heyd |
| author_sort | Marco Preussner |
| collection | DOAJ |
| description | Abstract Background 3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3′UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3′UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes. Results 3′UTR-encoded amino acid sequences show an enrichment of PxxP motifs and lead to interactome rewiring. Furthermore, an elevated proline content increases protein disorder and reduces protein stability, thus allowing splicing-controlled regulation of protein half-life. This could also act as a surveillance mechanism for erroneous skipping of penultimate exons resulting in transcripts that escape nonsense mediated decay. The impact of frameshift-inducing alternative splicing on disease development is emphasized by a retinitis pigmentosa-causing mutation leading to translation of a 3′UTR-encoded, proline-rich, destabilized frameshift-protein with altered protein-protein interactions. Conclusions We describe a widespread, evolutionarily conserved mechanism that enriches the mammalian proteome, controls protein expression and protein-protein interactions, and has important implications for the discovery of novel, potentially disease-relevant protein variants. |
| first_indexed | 2024-12-10T08:59:15Z |
| format | Article |
| id | doaj.art-2201d5578c144f41bc65e2e846538ab0 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-10T08:59:15Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-2201d5578c144f41bc65e2e846538ab02022-12-22T01:55:20ZengBMCGenome Biology1474-760X2020-07-0121112410.1186/s13059-020-02102-3Splicing-accessible coding 3′UTRs control protein stability and interaction networksMarco Preussner0Qingsong Gao1Eliot Morrison2Olga Herdt3Florian Finkernagel4Michael Schumann5Eberhard Krause6Christian Freund7Wei Chen8Florian Heyd9Institute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of RNA BiochemistryBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Laboratory for Systems Biology and Functional GenomicsInstitute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of Protein BiochemistryInstitute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of RNA BiochemistryCenter for Tumor Biology and Immunology (ZTI), Philipps-University MarburgLeibniz-Institut für Molekulare PharmakologieLeibniz-Institut für Molekulare PharmakologieInstitute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of Protein BiochemistryDepartment of Biology, South University of Science and Technology of ChinaInstitute of Chemistry and Biochemistry, Freie Universität Berlin, Laboratory of RNA BiochemistryAbstract Background 3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3′UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3′UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes. Results 3′UTR-encoded amino acid sequences show an enrichment of PxxP motifs and lead to interactome rewiring. Furthermore, an elevated proline content increases protein disorder and reduces protein stability, thus allowing splicing-controlled regulation of protein half-life. This could also act as a surveillance mechanism for erroneous skipping of penultimate exons resulting in transcripts that escape nonsense mediated decay. The impact of frameshift-inducing alternative splicing on disease development is emphasized by a retinitis pigmentosa-causing mutation leading to translation of a 3′UTR-encoded, proline-rich, destabilized frameshift-protein with altered protein-protein interactions. Conclusions We describe a widespread, evolutionarily conserved mechanism that enriches the mammalian proteome, controls protein expression and protein-protein interactions, and has important implications for the discovery of novel, potentially disease-relevant protein variants.http://link.springer.com/article/10.1186/s13059-020-02102-3Alternative splicing3′UTRProtein stabilityProtein disorderProtein-protein interactionAlternative open reading frame |
| spellingShingle | Marco Preussner Qingsong Gao Eliot Morrison Olga Herdt Florian Finkernagel Michael Schumann Eberhard Krause Christian Freund Wei Chen Florian Heyd Splicing-accessible coding 3′UTRs control protein stability and interaction networks Genome Biology Alternative splicing 3′UTR Protein stability Protein disorder Protein-protein interaction Alternative open reading frame |
| title | Splicing-accessible coding 3′UTRs control protein stability and interaction networks |
| title_full | Splicing-accessible coding 3′UTRs control protein stability and interaction networks |
| title_fullStr | Splicing-accessible coding 3′UTRs control protein stability and interaction networks |
| title_full_unstemmed | Splicing-accessible coding 3′UTRs control protein stability and interaction networks |
| title_short | Splicing-accessible coding 3′UTRs control protein stability and interaction networks |
| title_sort | splicing accessible coding 3 utrs control protein stability and interaction networks |
| topic | Alternative splicing 3′UTR Protein stability Protein disorder Protein-protein interaction Alternative open reading frame |
| url | http://link.springer.com/article/10.1186/s13059-020-02102-3 |
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