DAKAP1 signaling complexes coordinate local synthesis at the mitochondrial surface
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA575262 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10212874_1.fastq.gz | Fastqsanger.gz | |||
| SRR10212874_2.fastq.gz | Fastqsanger.gz | |||
| SRR10212875_1.fastq.gz | Fastqsanger.gz | |||
| SRR10212875_2.fastq.gz | Fastqsanger.gz | |||
| SRR10212876_1.fastq.gz | Fastqsanger.gz |
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Project description:We find that the KH domain of dAKAP1 binds mRNAs encoding proteins required for mitochondrial metabolism
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Project description:Compartmentalization of macromolecules is a ubiquitous molecular mechanism that drives numerous cellular functions. The appropriate organization of enzymes in space and time enables the precise transmission and integration of intracellular signals. Molecular scaffolds constrain signaling enzymes to influence the regional modulation of these physiological processes. Mitochondrial targeting of protein kinases and protein phosphatases provides a means to locally control the phosphorylation status and action of proteins on the surface of this organelle. Dual-specificity protein kinase A anchoring protein 1 (dAKAP1) is a multivalent binding protein that targets protein kinase A (PKA), RNAs, and other signaling enzymes to the outer mitochondrial membrane. Many AKAPs recruit a diverse set of binding partners that coordinate a broad range of cellular processes. Here, results of MS and biochemical analyses reveal that dAKAP1 anchors additional components, including the ribonucleoprotein granule components La-related protein 4 (LARP4) and polyadenylate-binding protein 1 (PABPC1). Local translation of mRNAs at organelles is a means to spatially control the synthesis of proteins. RNA-Seq data demonstrate that dAKAP1 binds mRNAs encoding proteins required for mitochondrial metabolism, including succinate dehydrogenase. Functional studies suggest that the loss of dAKAP1-RNA interactions reduces mitochondrial electron transport chain activity. Hence, dAKAP1 plays a previously unappreciated role as a molecular interface between second messenger signaling and local protein synthesis machinery.
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Project description:Cells harbor two systems for the synthesis of fatty acids, one in the cytoplasm (FASN or fatty acid synthase) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, with the major product(s), metabolic roles, and cellular function(s) essentially unknown. Here we show that hypomorphic mtFAS mutants display a profound loss of electron transport chain (ETC) complexes and exhibit compensatory reductive carboxylation. This effect on ETC complexes is independent of the synthesis of lipoic acid, the best characterized function of mtFAS, as mutants lacking lipoic acid synthesis have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. These data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels.
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Project description:Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. Here we identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of mRNA translation in a cell type-specific and synapse type-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV+ interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system.
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Project description:Regulated local synthesis of ribosomal proteins maintains ribosome function in axons
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Project description:Oxidative phosphorylation (OXPHOS) complexes consist of nuclear- and mitochondrial- encoded subunits, forcing cross-compartment synchronization of gene expression to achieve mitonuclear balance. To characterize how human cells coordinate OXPHOS gene expression, we establish a mitoribosome profiling approach that resolves features of the mitochondrial translatome, including the synthesis of a four amino acid mitopeptide. Strikingly, average mitochondrial and cytoplasmic synthesis rates correspond precisely across OXPHOS complexes. Coordinated mitochondrial and cytosolic synthesis does not require rapid feedback between the two translation systems. By contrast, we find that the Leigh syndrome gene, LRPPRC, maintains correlated mitochondrial and cytosolic translatomes. Our results lead to a model of human mitonuclear balance that requires tightly balanced cross-compartment protein synthesis, representing a vulnerability for cellular proteostasis.
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Project description:Terminal oligopyrimidine motif-containing (TOP) mRNAs encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies implicate LARP1 in 40S- or 80S-ribosome complexes that repress and stabilize TOP mRNAs. However, a mechanistic understanding of how LARP1 and TOP mRNAs interact with ribosomes to coordinate TOP mRNA outcomes is lacking. Here, we show that LARP1 senses the cellular supply of ribosomes by directly binding non-translating 80S ribosomes. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the 40S mRNA channel and mutations at the LARP1-ribosome interface block formation of the 40S/80S-LARP1-TOP complexes. Free cytosolic ribosomes induce sequestration of TOP mRNAs in repressed 80S-LARP1-TOP complexes independent of alterations in mTOR signaling. Together, this work demonstrates a ribosome-sensing function of LARP1 that allows it to tune ribosome protein synthesis to the availability of free ribosomes.
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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.
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Project description:Motoneurons critically depend on precise spatial and temporal control of translation for axon growth and the establishment and maintenance of neuromuscular connections. While defects in local translation have been implicated in the pathogenesis of motoneuron disorders, little is known about the mechanisms regulating axonal protein synthesis. Here, we report that motoneurons derived from Hnrnpr knockout mice show reduced axon growth accompanied by lowered synthesis of cytoskeletal and synaptic components in axons. Mutant mice display denervated neuromuscular junctions and impaired motor behavior. In axons, hnRNP R is a component of translation initiation complexes and, through interaction with O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (Ogt), modulates O-GlcNAcylation of eIF4G. Restoring axonal O-GlcNAc levels rescued local protein synthesis and axon growth defects of hnRNP R knockout motoneurons. Together, these findings demonstrate a function of hnRNP R in controlling the local production of key factors required for axon growth and formation of neuromuscular innervations.
2024-07-24 | GSE242027 | GEO
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.
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