Splicing-accessible coding 3′UTRs control protein stability and interaction networks

Preussner，Marco1; Gao，Qingsong2; Morrison，Eliot3; Herdt，Olga1; Finkernagel，Florian4; Schumann，Michael5; Krause，Eberhard5; Freund，Christian3; Chen，Wei6; Heyd，Florian1

2020-07-29

10.1186/s13059-020-02102-3

Genome Biology   影响因子和分区

1474-7596

1474-760X

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.

3′UTR Alternative open reading frame Alternative splicing Genome structure Protein disorder Protein stability Protein-protein interaction

SCI

英语

通讯

Deutsche Forschungsgemeinschaft[HE 5398/7-1][HE5398/4-2] ; DFG[278001972 -TRR 186] ; Senate of Berlin, Berlin, Germany[BIMSB 0315362A][0315362C]

Biotechnology & Applied Microbiology ; Genetics & Heredity

Biotechnology & Applied Microbiology ; Genetics & Heredity

WOS:000557561900001

BMC

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85088851898

Scopus

1.Institute of Chemistry and Biochemistry,Freie Universität Berlin,Laboratory of RNA Biochemistry,Berlin,Takustrasse 6,14195,Germany
2.Berlin Institute for Medical Systems Biology,Max Delbrück Center for Molecular Medicine,Laboratory for Systems Biology and Functional Genomics,Berlin,Robert-Rössle-Str. 10,13125,Germany
3.Institute of Chemistry and Biochemistry,Freie Universität Berlin,Laboratory of Protein Biochemistry,Berlin,Thielallee 63,14195,Germany
4.Center for Tumor Biology and Immunology (ZTI),Philipps-University Marburg,Marburg,Hans-Meerwein-Straße 3,35043,Germany
5.Leibniz-Institut für Molekulare Pharmakologie,Berlin,Robert-Rössle-Strasse 10,13125,Germany
6.Department of Biology,South University of Science and Technology of China,Shenzhen Guangdong,China

Preussner，Marco,Gao，Qingsong,Morrison，Eliot,等. Splicing-accessible coding 3′UTRs control protein stability and interaction networks[J]. Genome Biology,2020,21(1).

Preussner，Marco.,Gao，Qingsong.,Morrison，Eliot.,Herdt，Olga.,Finkernagel，Florian.,...&Heyd，Florian.(2020).Splicing-accessible coding 3′UTRs control protein stability and interaction networks.Genome Biology,21(1).

Preussner，Marco,et al."Splicing-accessible coding 3′UTRs control protein stability and interaction networks".Genome Biology 21.1(2020).