Progranulin Transcripts with Short and Long 5′ Untranslated Regions (UTRs) Are Differentially Expressed via Posttranscriptional and Translational Repression
| Autor: | Christian Haass, Anja Capell, Katrin Fellerer |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Untranslated region
metabolism [Intercellular Signaling Peptides and Proteins] Five prime untranslated region Biochemistry genetics [Peptide Chain Termination Translational] Progranulins Neurobiology Protein Isoforms 3' Untranslated Regions Genetics genetics [Intercellular Signaling Peptides and Proteins] Translation (biology) respiratory system DNA-Binding Proteins genetics [Amyotrophic Lateral Sclerosis] ddc:540 genetics [3' Untranslated Regions] Intercellular Signaling Peptides and Proteins genetics [Frontotemporal Lobar Degeneration] metabolism [DNA-Binding Proteins] genetics [Protein Isoforms] Translational efficiency genetics [5' Untranslated Regions] genetics [DNA-Binding Proteins] Biology behavioral disciplines and activities genetics [RNA Messenger] Open Reading Frames mental disorders Upstream open reading frame Humans RNA Messenger pathology [Amyotrophic Lateral Sclerosis] Molecular Biology Psychological repression pathology [Frontotemporal Lobar Degeneration] Three prime untranslated region metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis Cell Biology Peptide Chain Termination Translational metabolism [Frontotemporal Lobar Degeneration] nervous system diseases Open reading frame HEK293 Cells nervous system Gene Expression Regulation Mutation GRN protein human Frontotemporal Lobar Degeneration 5' Untranslated Regions |
| Zdroj: | The journal of biological chemistry 289(37), 25879-25889 (2014). doi:10.1074/jbc.M114.560128 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m114.560128 |
| Popis: | Frontotemporal lobar degeneration is associated with cytoplasmic or nuclear deposition of the TAR DNA-binding protein 43 (TDP-43). Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for frontotemporal lobar degeneration associated with TDP-43 deposition. Therefore, understanding the mechanisms that control cellular expression of GRN is required not only to understand disease etiology but also for the development of potential therapeutic strategies. We identified different GRN transcripts with short (38-93 nucleotides) or long (219 nucleotides) 5' UTRs and demonstrate a cellular mechanism that represses translation of GRN mRNAs with long 5' UTRs. The long 5' UTR of GRN mRNA contains an upstream open reading frame (uORF) that is absent in all shorter transcripts. Because such UTRs can be involved in translational control as well as in mRNA stability, we compared the expression of GRN in cells expressing cDNAs with and without 5' UTRs. This revealed a selective repression of GRN translation and a reduction of mRNA levels by the 219-nucleotide-long 5' UTR. The specific ability of this GRN 5' UTR to repress protein expression was further confirmed by its transfer to an independent reporter. Deletion analysis identified a short stretch between nucleotides 76 and 125 containing two start codons within one uORF that is required and sufficient for repression of protein expression. Mutagenesis of the two AUG codons within the uORF is sufficient to reduce translational repression. Therefore initiating ribosomes at the AUGs of the uORF fail to efficiently initiate translation at the start codon of GRN. In parallel the 5' UTR also affects mRNA stability; thus two independent mechanisms determine GRN expression via mRNA stability and translational efficiency. |
| Databáze: | OpenAIRE |
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