Genetic depletion of the RNA helicase DDX3 leads to impaired elongation of translating ribosomes triggering co-translational quality control of newly synthesized polypeptides
| Autor: | Filipe Colaço Mariz, Prasad K. Padmanabhan, Barbara Papadopoulou, Carole Dumas, Camila Oliveira, Ouafa Zghidi-Abouzid, Gabriel Reis Ferreira |
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| Rok vydání: | 2021 |
| Předmět: |
Peptide Biosynthesis
Ribosomal Proteins AcademicSubjects/SCI00010 Ubiquitin-Protein Ligases Ribosome Recycling Factor Biology Ribosome 03 medical and health sciences Eukaryotic translation Ubiquitin Genetics Protein biosynthesis RNA and RNA-protein complexes Humans HSP70 Heat-Shock Proteins Leishmania infantum 030304 developmental biology 0303 health sciences 030302 biochemistry & molecular biology Translation (biology) RNA Helicase A Hsp70 Cell biology Protein Biosynthesis biology.protein Peptides Ribosomes RNA Helicases Protein Modification Translational |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | DDX3 is a multifaceted RNA helicase of the DEAD-box family that plays central roles in all aspects of RNA metabolism including translation initiation. Here, we provide evidence that the Leishmania DDX3 ortholog functions in post-initiation steps of translation. We show that genetic depletion of DDX3 slows down ribosome movement resulting in elongation-stalled ribosomes, impaired translation elongation and decreased de novo protein synthesis. We also demonstrate that the essential ribosome recycling factor Rli1/ABCE1 and termination factors eRF3 and GTPBP1 are less recruited to ribosomes upon DDX3 loss, suggesting that arrested ribosomes may be inefficiently dissociated and recycled. Furthermore, we show that prolonged ribosome stalling triggers co-translational ubiquitination of nascent polypeptide chains and a higher recruitment of E3 ubiquitin ligases and proteasome components to ribosomes of DDX3 knockout cells, which further supports that ribosomes are not elongating optimally. Impaired elongation of translating ribosomes also results in the accumulation of cytoplasmic protein aggregates, which implies that defects in translation overwhelm the normal quality controls. The partial recovery of translation by overexpressing Hsp70 supports this possibility. Collectively, these results suggest an important novel contribution of DDX3 to optimal elongation of translating ribosomes by preventing prolonged translation stalls and stimulating recycling of arrested ribosomes. |
| Databáze: | OpenAIRE |
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