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Regulated local synthesis of ribosomal proteins maintains ribosome function in axons

ABSTRACT: Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE135502 | GEO | 2019/12/11

REPOSITORIES: GEO

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Regulated local synthesis of ribosomal proteins maintains ribosome function in axons

Project description:Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.

2019-12-09 | PXD015574 | Pride

Transcriptome and translatome of ribosomal protein-deficient human cells

Project description:Human ribosomes are made of around 80 ribosomal proteins (RPs) and four ribosomal RNAs. To explore gene expression regulation by RPs at the transcriptional and translational levels, parallel RNA-seq and Ribo-seq were conducted in A549 cells after knockdown of individual RP.

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SILAC-labeled proteins in ribosome samples

Project description:we developed a novel method combining axon-pSILAC17 with axonal ribosome purification. In this method, we first labeled newly synthesized proteins with heavy amino acids (AAs) in somaless axons cultured in a Boyden chamber. Approximately 2000 eyes were cultured for each experiment to obtain sufficient axonal material. Then, axonal ribosomes were purified using a sucrose cushion and ultracentrifugation, followed by identification of newly synthesized proteins with mass spectrometry.

2019-12-09 | PXD011032 | Pride

Neuronal ribosomes dynamically exchange ribosomal proteins in a context-dependent manner.

Project description:Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs rapidly associated with translating ribosomes in the cytoplasm and that this incorporation is independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (following oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing neuronal synapses a rapid means to regulate local protein synthesis.

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The dynamic translatome of retinal ganglion cell axons during assembly and maintenance of the mouse visual system

Project description:Local mRNA translation mediates the adaptive responses of axons to extrinsic signals but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles suggesting distinct steps in axon wiring, such as elongation, pruning and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and novel sequence elements generated by alternative splicing that promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo. The profiling of ribosome-bound mRNAs in mouse retinal ganglion cell axons at 4 different developmental stages

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Heterogeneous ribosomes exist and selectively translate distinct subpools of mRNAs in stem cells

Project description:Emerging studies have linked the ribosome to more selective control of gene regulation. However, an outstanding question is whether ribosome heterogeneity at the level of core ribosomal proteins (RPs) enables ribosomes to preferentially translate specific mRNAs genome-wide. Here, we measured the absolute abundance of RPs in translating ribosomes and profiled transcripts that are enriched or depleted from select subsets of ribosomes within embryonic stem cells. We find that heterogeneity in RP composition endows ribosomes with different selectivity for translating subpools of transcripts including those controlling metabolism, the cell cycle, and development. As a paradigm example, we show that mRNAs enriched in binding to RPL10A/uL1-containing ribosomes require RPL10A/uL1 for their efficient translation. Within several of these transcripts, we find this level of regulation is mediated, at least in part, by internal ribosome entry sites. Together, these results reveal a critical functional link between ribosome heterogeneity and the post-transcriptional circuitry of gene expression.

2017-06-15 | GSE73357 | GEO

The dynamic translatome of retinal ganglion cell axons during assembly and maintenance of the mouse visual system

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Cold Triggered Paralog Rearrangements Indicate Potential Ribosome Specialization in Arabidopsis thaliana

Project description:Plant ribosomes are heterogeneous due to genome duplications that resulted in several paralog genes encoding each ribosomal protein (RP). The mainstream view suggests that heterogeneity provides sufficient ribosomes throughout the Arabidopsis lifespan without any functional implications. Nevertheless, genome duplications are known to produce sub- and neofunctionalization of initially redundant genes. Functional divergence of RP paralogs can be considered ribosome specialization if the diversified functions of these paralogs remain within the context of protein translation, especially if RP divergence should contribute to a preferential or ultimately even rigorous selection of transcripts to be translated by a RP-defined ribosome subpopulation. Here we provide evidence that cold acclimation triggers a reprogramming in structural RPs at the transcriptome and proteome level. The reprogramming alters the abundance of RPs or RP paralogs in non-translational 60S large subunits (LSUs) and translational polysome fractions, a phenomenon known as substoichiometry. Cold triggered substoichiometry of ribosomal complexes differ once Arabidopsis REIL-like mediated late maturation step for the LSU is impaired. Interestingly, remodeling of ribosomes after a cold stimulus appears to be significantly constrained to specific spatial regions of the ribosome. The regions that are significantly changed during cold acclimation as judged by transcriptome or proteome data include the polypeptide exit tunnel and the P-Stalk. Both substructures of the ribosome represent plausible targets of mechanisms that may constrain translation by controlled ribosome heterogeneity. This work represents a step forward towards understanding heterogeneity and potential specialization of plant ribosomal complexes.

2021-06-28 | PXD016292 | Pride

The 40S-LARP1 complex reprograms the cellular translatome upon mTOR inhibition to preserve the protein synthetic capacity

Project description:Ribosomes execute the transcriptional program in every cell. Critical to sustain nearly all cellular activities, ribosome biogenesis requires the translation of ~200 factors of which 80 are ribosomal proteins (RPs). As ribosome synthesis depends on RP mRNAs translation, a priority within the translatome architecture should exist to ensure the preservation of ribosome biogenesis capacity, particularly under adverse growth conditions. Here we show that under critical metabolic constraints characterized by mTOR inhibition, LARP1 complexed with the 40S subunit protects from ribophagy the mRNAs regulon for ribosome biogenesis and protein synthesis, acutely preparing the translatome to promptly resume ribosomes production after growth conditions return permissive. Characterizing the LARP1-protected translatome revealed a set of 5’TOP transcript isoforms other than RPs involved in energy production and in mitochondrial function, among other processes, indicating that the mTOR-LARP1-5’TOP axis acts at the translational level as a primary guardian of the cellular anabolic capacity

2021-10-30 | GSE186779 | GEO

A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

Project description:Ribosome biogenesis is a complex and energy-demanding process requiring tight coordination of ribosomal RNA (rRNA) and ribosomal protein (RP) production. Alteration of any step in this process may impact growth by leading to proteotoxic stress. Although the transcription factor Hsf1 has emerged as a central regulator of proteostasis, how its activity is coordinated with ribosome biogenesis is unknown. Here we show that arrest of ribosome biogenesis in the budding yeast S. cerevisiae triggers rapid activation of a highly specific stress pathway that coordinately up-regulates Hsf1 target genes and down-regulates RP genes. Activation of Hsf1 target genes requires neo-synthesis of RPs, which accumulate in an insoluble fraction, leading to sequestration of the RP transcriptional activator Ifh1. Our data suggest that levels of newly-synthetized RPs, imported into the nucleus but not yet assembled into ribosomes, work to continuously balance Hsf1 and Ifh1 activity, thus guarding against proteotoxic stress during ribosome assembly.

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