RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA838484 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19217100.fastq.gz | Fastqsanger.gz | |||
| SRR19217101.fastq.gz | Fastqsanger.gz | |||
| SRR19217102.fastq.gz | Fastqsanger.gz | |||
| SRR19217103.fastq.gz | Fastqsanger.gz | |||
| SRR19217054.fastq.gz | Fastqsanger.gz |
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Project description:Although several ribosomal protein (RP) paralogs are expressed in a tissue-specific manner, how these proteins affect translation and why they are required only in certain tissues have remained unclear. Here we show that RPL3L, a paralog of RPL3 specifically expressed in heart and skeletal muscle, influences translation elongation dynamics. Deficiency of RPL3L-containing ribosomes (RPL3L-ribosomes) in RPL3L knockout male mice resulted in impaired cardiac contractility. Ribosome occupancy at mRNA codons was found to be altered in the RPL3L-deficient heart, and the changes were negatively correlated with those observed in myoblasts overexpressing RPL3L. RPL3L-ribosomes were less prone to collisions compared with RPL3-containing canonical ribosomes. Although the loss of RPL3L-ribosomes altered translation elongation dynamics for the entire transcriptome, its effects were most pronounced for transcripts related to cardiac muscle contraction and dilated cardiomyopathy, with the abundance of the encoded proteins being correspondingly decreased. Our results provide new insight into the mechanisms and physiological relevance of tissue-specific translational regulation.
2023-03-15 | GSE203072 | GEO
Project description: Not available
| S-EPMC10119107 | biostudies-literature
Project description:RPL3L-containing ribosomes modulate mitochondrial activity in the mammalian heart.
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Project description:Local protein synthesis is a crucial process that maintains synaptic proteostasis. Ribosomes stalled at elongation make up a sizable percentage of mRNAs translated in developing neurons. The protein lost in Fragile X syndrome (FMRP) is highly enriched in RNA granules containing stalled ribosomes, both of which play crucial roles in regulating forms of synaptic plasticity such as metabotropic glutamate receptor-dependent long-term depression (mGLUR-LTD). Previous examination of ribosome protected fragments (RPFs) from neuronal stalled ribosomes have identified motifs matching those found in mRNAs associated with FMRP, as recognized by FMRP cross-linking immunoprecipitation (CLIP) (Anadolu et al., 2023, Journal of Neuroscience doi: 10.1523/JNEUROSCI.1002-22.2023). To investigate if FMRP recognition of these sequences is important for determining where mRNAs are stalled, we examined stalled ribosomes RPFs isolated from P5 mice lacking the FMRP protein. We found that the loss of FMRP had no effect on the proteins associated with RNA granules, structure of the ribosomes and stalling sites, or where accumulations of RPFs occurred. However, there was a significant decrease in the amount of stalling on mRNAs previously shown to be associated with FMRP by cross-linking immunoprecipitation (CLIP). In addition, there was a decrease in the number of RNA granules containing stalled polysomes as assayed by ribopuromycylation in distal neurites and, unlike RNA granules in WT neurons, the remaining distal RNA granules were resistant to reactivation by stimuli that induce mGLuR-LTD. These results show important roles for FMRP in regulating RNA granules containing stalled ribosomes, but not in determining where ribosomes are stalled.
2026-06-18 | GSE291701 | GEO
Project description:Overall goal: To elucidate the function served by Rpl3L in heart. Purpose of analysis: To determine effects of Rpl3L-deficiency on translational mRNA profile in heart. Experimental structure: Polysomes and monosomes were fractionated from cardiac ventricles and associated RNA extracted for library generation and differential gene expression analyses between wild-type and Rpl3L-null samples, using standard RNAseq pipeline.
2023-02-10 | GSE215869 | GEO
Project description:FMRP Regulates Neuronal RNA Granules Containing Stalled Ribosomes, Not Where Ribosomes Stall
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Project description:The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by rare biallelic variants in RPL3L, a muscle-specific ribosomal protein that replaces the ubiquitous RPL3 in cardiac ribosomes. RPL3L-linked heart failure represents the only known human disease arising from mutations in tissue-specific ribosomes, yet the underlying pathogenetic mechanisms remain poorly understood despite an increasing number of reported cases. While the autosomal recessive inheritance pattern suggests a loss-of-function mechanism, Rpl3l-knockout mice display only mild phenotypes, attributed to up-regulation of the ubiquitous Rpl3. Interestingly, living human knockouts of RPL3L have been identified. Here, we report two new cases of RPL3L-linked severe neonatal heart failure and uncover an unusual pathogenetic mechanism through integrated analyses of population genetic data, patient cardiac tissue, and isogenic cells expressing RPL3L variants. Our findings demonstrate that patient hearts lack sufficient RPL3 compensation. Moreover, contrary to a simple loss-of-function mechanism often associated with autosomal recessive diseases, RPL3L-linked disease is driven by a combination of gain-of-toxicity and loss-of-function. Most patients harbor a recurrent toxic missense variant alongside a non-recurrent variant. The non-recurrent variant is often loss-of-function and enables partial compensation through RPL3, similar to Rpl3l-knockout mice. However, the recurrent missense variant exhibits increased affinity for the RPL3/RPL3L chaperone GRWD1 and 60S biogenesis factors, retains 28S rRNA in the nucleus, disrupts ribosome biogenesis, and induces severe cellular toxicity that extends beyond the loss of ribosomes. These findings elucidate the pathogenetic mechanisms underlying muscle-specific ribosome dysfunction in neonatal heart failure, providing critical insights for genetic screening and therapeutic development. Our findings also suggest that gain-of-toxicity mechanisms may be more widespread in autosomal recessive diseases, especially for those involving genes with paralogs.
2025-11-14 | GSE302553 | GEO
Project description:Mutations in the tissue-specific ribosomal protein RPL3L lead to infant dilated cardiomyopathy. The current project aims to understand the mechanistic details of disease progression using in vivo biopsies from transplanted heart of patient with RPL3L mutations as well as engineered AC16 cell lines that express the same and other RPL3L variants containing a C-terminal HA tag. The files consist of two datasets from human left ventricle (LV) and human AC16 cells, respectively. The human LV samples are two technical replicates from the same biopsy. The AC16 cell samples are immunoprecipitations of HA-tagged RPL3L in nuclear extracts.
2025-11-15 | PXD066450 | Pride
Project description:The ribosomal protein L3-like (RPL3L) is a striated muscle-specific ribosomal protein, and mutations in human RPL3L are linked with childhood cardiomyopathy and age-related atrial fibrillation. However, the function served by this protein, a paralogue of the ubiquitously expressed RPL3 protein, remains poorly characterized in both heart and skeletal muscle. To address this, null mutant mice with the Rpl3L gene deleted were generated and studied. The purpose of this microarray analyses was to compare transcriptional profiles of the null mutant hearts (lacking RPL3L) with wild-type control hearts (expressing RpL3L). We used microarrays to elucidate effects of Rpl3L deficiency on transcriptional profile of mouse hearts
2023-02-10 | GSE216168 | GEO
Project description:To measure absolute abundance of paralogs, AC16 (RPL3+) and shRPL3/RPL3L+ (RPL3L-WT) cells were treated with 400ng/ml doxycycline for 8 days. Cells were pelleted and submitted for label free mass spectrometry.
2025-11-15 | PXD066930 | Pride