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FUS contributes to mTOR-dependent inhibition of translation.

ABSTRACT: The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

SUBMITTER: Sevigny M

PROVIDER: S-EPMC7939483 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Protein synthesis is an energy-demanding process essential for cell proliferation and survival. Balancing the cost of protein synthesis with available resources has driven the evolution of its nutrient-dependent regulation. A central mechanism in this regulation is the repression of translation of the protein synthesis machinery during unfavorable growth conditions. This is mediated via mammalian target of rapamycin (mTOR), a master regulator of growth conserved from yeast to human. Despite extensive research, and the elucidation of a number of important factors, how mRNAs are translationally regulated by mTOR is still unclear. Repression depends on a 5’ Terminal Oligo Pyrimidine (TOP) motif which is conserved across vertebrates and present in Drosophila melanogaster. In Caenorhabditis elegans and the marine chordate Oikopleura dioica most TOP mRNAs are trans-spliced to a spliced leader. This results in the removal of the originally transcribed 5’ end and its replacement with a common short RNA sequence. In both species the 5’ end of the spliced leader is pyrimidine-enriched but does not meet strict requirements for a canonical TOP motif. How this affects the translational control of TOP mRNAs is unknown. Here, using transcriptome-wide ribosome profiling on whole animals treated with the mTOR inhibitor Torin 1, we show that trans-spliced TOP mRNAs in O. dioica are subject to mTOR-dependent translational control. We also show, using existing data, that trans-spliced transcripts in C. elegans are differentially translated upon recovery from starvation-induced developmental diapause. Together our results demonstrate that spliced leaders in metazoans are targets for mTOR-dependent translational control in response to nutrient availability. This indicates that trans-splicing in metazoans, the function of which has remained largely enigmatic, plays a key role in the coordinated translational regulation of growth-related genes. Moreover, our results reveal an innovative strategy for rapid evolution and developmental control of downstream targets of the ancient mTOR pathway.

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FUS contributes to mTOR-dependent inhibition of translation.

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