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Co-translational regulation of Mmf1 expression depends upon its mitochondrial targeting, ubiquitination of Egd1 by Not4, Caf130 and NGD: MitoENCay

ABSTRACT: Co-translational regulation of Mmf1 expression depends upon its mitochondrial targeting, ubiquitination of Egd1 by Not4, Caf130 and NGD: MitoENCay

PROVIDER: PRJNA853180 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19858376.fastq.gz	Fastqsanger.gz
	SRR19858377.fastq.gz	Fastqsanger.gz
	SRR19858378.fastq.gz	Fastqsanger.gz
	SRR19858379.fastq.gz	Fastqsanger.gz

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Co-translational regulation of Mmf1 expression depends upon its mitochondrial targeting, ubiquitination of Egd1 by Not4, Caf130 and NGD: MitoENCay

Project description:The Ccr4-Not complex is a conserved multi protein complex with diverse roles in the mRNA life cycle. Recently we determined that the Not1 and Not4 subunits of Ccr4-Not inversely regulate mRNA solubility and thereby impact dynamics of co-translation events. One mRNA whose solubility is most extremely inversely regulated by Not1 and Not4 is MMF1 encoding a mitochondrial protein that is translated with apparent ribosome pausing. In this work we uncover a mechanism that limits MMF1 overexpression in fermenting yeast and does not require MMF1 5’ or 3’ untranslated sequences but is mediated solely by the MMF1 coding sequence. This mechanism depends upon co-translational targeting of the MMF1 mRNA to the mitochondria, promoted by its mitochondrial targeting sequence, the Egd1 subunit of the NAC complex, the Om14 outer membrane protein and components of the mitochondrial import machinery as well as by Not4. Thereby, levels and translation of the MMF1 mRNA are limited by a mechanism that we have named Mito-ENCay involving ubiquitination of Egd1 by Not4, the Caf130 subunit of the Ccr4-Not complex and RQC. Our results indicate that this mechanism is used for highly expressed mRNAs that depend upon co-translational interactions for appropriate folding, such as ribosomal protein mRNAs in fermenting yeast.

2025-02-13 | GSE206973 | GEO

Ribosomal protein S7 ubiquitination during ER stress in yeast is associated with selective mRNA translation and stress outcome.

Project description:eIF2α phosphorylation-mediated translational regulation is crucial for global translation repression by various stresses, including the unfolded protein response (UPR). However, translational control during UPR has not been demonstrated in yeast. This study investigated ribosome ubiquitination-mediated translational controls during UPR. Tunicamycin-induced ER stress enhanced the levels of ubiquitination of the ribosomal proteins uS10, uS3 and eS7. Not4-mediated monoubiquitination of eS7A was required for resistance to tunicamycin, whereas E3 ligase Hel2-mediated ubiquitination of uS10 was not. Ribosome profiling showed that the monoubiquitination of eS7A was crucial for translational regulation, including the upregulation of the spliced form of HAC1 (HAC1i) mRNA and the downregulation of Histidine triad NucleoTide-binding 1 (HNT1) mRNA. Downregulation of the deubiquitinating enzyme complex Upb3-Bre5 increased the levels of ubiquitinated eS7A during UPR in an Ire1-independent manner. These findings suggest that the monoubiquitination of ribosomal protein eS7A plays a crucial role in translational controls during the ER stress response in yeast.

2020-11-12 | GSE128578 | GEO

Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events

Project description:Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events

| PRJNA798390 | ENA

Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events

Project description:Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events

| PRJNA787934 | ENA

Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy.

Project description:Translation of mRNAs is tightly regulated and constantly surveyed for errors. Aberrant translation can trigger co-translational protein and RNA quality control processes, impairments of which cause neurodegeneration by still poorly understood mechanism(s). Here we show that quality control of translation of mitochondrial outer membrane (MOM)-localized mRNA intersects with the turnover of damaged mitochondria, both orchestrated by the mitochondrial kinase PINK1. Mitochondrial damage causes stalled translation of complex-I 30 kDa subunit (C-I30) mRNA on MOM, triggering the recruitment of co-translational quality control factors Pelo, ABCE1, and NOT4 to the ribosome/mRNA-ribonucleoprotein complex. Damage-induced ubiquitination of ABCE1 by NOT4 generates poly-ubiquitin signals that attract autophagy receptors to MOM to initiate mitophagy. In the Drosophila PINK1 model, these factors act synergistically to restore mitophagy and neuromuscular tissue integrity. Thus ribosome-associated co-translational quality control generates an early signal to trigger mitophagy. Our results have broad therapeutic implications for the understanding and treatment of neurodegenerative diseases.

| S-EPMC5989559 | biostudies-literature

Not4 and Not5 modulate translation elongation by Rps7A ubiquitination, Rli1 moonlighting, and condensates that exclude eIF5A

Project description:Not4 and Not5 modulate translation elongation by Rps7A ubiquitination, Rli1 moonlighting, and condensates that exclude eIF5A

| PRJNA565947 | ENA

The Not4 ubiquitin ligase utilizes its conserved RNA binding domains to regulate global proteostasis and RNA polymerase II-dependent transcription

Project description:The conserved Ccr4-Not complex regulates all aspects of the RNA polymerase II (Pol II) gene expression pathway, while it also controls proteasome assembly and function. The Not4 RING domain ubiquitin ligase is a core subunit that also contains an RNA recognition motif (RRM) and C3H1 domain (collectively referred to as the RRM-C) whose function is unknown. Herein, we demonstrate that the Not4 RRM-C contributes to both Not4-dependent regulation of the proteasome and Pol II. Disruption of both Not4 ligase activity and the RRM-C domain simultaneously replicates the proteasome-dependent deubiquitylation and catalytic activity misregulation found in Not4-deficient cells. Transcriptome analysis reveals that the Not4 RRM-C affects a subset of Pol II-dependent genes involved in specific biological functions, including transcription elongation, cyclin-dependent kinase regulated nutrient responses, and ribosomal biogenesis. At these genes, the Not4 RRM-C negatively regulates Pol II binding. While Not4 RRM-C disruption modestly increases between Ccr4-Not and Pol II, a Not4 ligase mutant decreases Ccr4-Not association with Pol II, thus implicating Not4-dependent ubiquitylation in mediating Ccr4-Not interaction with Pol II. Collectively, our results suggests the cellular RNA environment may integrate control of global proteostasis and Pol II transcription through the Not4 ubiquitin ligase.

2017-08-03 | GSE102192 | GEO

Translation switch from initiation to elongation needs Not4 and Not5 collaboration

Project description:Not4 and Not5 are crucial components of the Ccr4-Not complex with pivotal functions in mRNA metabolism. Both associate with ribosomes but mechanistic insights on their function remain elusive. Here we determine that Not5 and Not4 synchronously impact translation initiation and Not5 alone alters translation elongation. Deletion of Not5 causes elongation defects in a codon-dependent fashion, increasing and decreasing the ribosome dwelling occupancy at minor and major codons respectively. This enhanced difference in codon translation velocities alters translation globally and enables normally kinetically unfavorable processes such as nascent chain deubiquitination to take place. In turn this leads to abortive translation and favors protein aggregation. These findings highlight the global impact of Not4 and Not5 in controlling the programmed local speed of mRNA translation.

2021-08-18 | GSE137613 | GEO

Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events

Project description:The goal is to compare role of Not1,4,5 in co-translational decay and solubility of RNAs from soluble and total RNA pools using degron strains

2023-01-24 | GSE193912 | GEO

Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events.

Project description:BackgroundThe Ccr4-Not complex is mostly known as the major eukaryotic deadenylase. However, several studies have uncovered roles of the complex, in particular of the Not subunits, unrelated to deadenylation and relevant for translation. In particular, the existence of Not condensates that regulate translation elongation dynamics has been reported. Typical studies that evaluate translation efficiency rely on soluble extracts obtained after the disruption of cells and ribosome profiling. Yet cellular mRNAs in condensates can be actively translated and may not be present in such extracts.ResultsIn this work, by analyzing soluble and insoluble mRNA decay intermediates in yeast, we determine that insoluble mRNAs are enriched for ribosomes dwelling at non-optimal codons compared to soluble mRNAs. mRNA decay is higher for soluble RNAs, but the proportion of co-translational degradation relative to the overall mRNA decay is higher for insoluble mRNAs. We show that depletion of Not1 and Not4 inversely impacts mRNA solubilities and, for soluble mRNAs, ribosome dwelling according to codon optimality. Depletion of Not4 solubilizes mRNAs with lower non-optimal codon content and higher expression that are rendered insoluble by Not1 depletion. By contrast, depletion of Not1 solubilizes mitochondrial mRNAs, which are rendered insoluble upon Not4 depletion.ConclusionsOur results reveal that mRNA solubility defines the dynamics of co-translation events and is oppositely regulated by Not1 and Not4, a mechanism that we additionally determine may already be set by Not1 promoter association in the nucleus.

| S-EPMC9940351 | biostudies-literature

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