The contribution of ribosome heterogeneity and ribosome-associated proteins to the molecular control of proteomes in health and disease remains unclear. Here, we demonstrate that survival motor neuron (SMN) protein-the loss of which causes the neuromuscular disease spinal muscular atrophy (SMA)-binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs that are enriched for translational enhancer sequences in the 5 ' untranslated region (UTR) and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins that are involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs encoding proteins that are relevant to SMA pathogenesis.Lauria et al. show that SMN, the loss of which causes spinal muscular atrophy (SMA), preferentially positions ribosomes within the first five codons of SMA-related mRNAs and enhances their translation.

SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy / Lauria, Fabio; Bernabo, Paola; Tebaldi, Toma; Groen, Ewout Joan Nicolaas; Perenthaler, Elena; Maniscalco, Federica; Rossi, Annalisa; Donzel, Deborah; Clamer, Massimiliano; Marchioretto, Marta; Omersa, Neza; Orri, Julia; Dalla Serra, Mauro; Anderluh, Gregor; Quattrone, Alessandro; Inga, Alberto; Gillingwater, Thomas Henry; Viero, Gabriella. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 22:10(2020), pp. 1239-1251. [10.1038/s41556-020-00577-7]

SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy

Lauria, Fabio;Tebaldi, Toma;Maniscalco, Federica;Rossi, Annalisa;Donzel, Deborah;Clamer, Massimiliano;Marchioretto, Marta;Quattrone, Alessandro;Inga, Alberto;Viero, Gabriella
2020

Abstract

The contribution of ribosome heterogeneity and ribosome-associated proteins to the molecular control of proteomes in health and disease remains unclear. Here, we demonstrate that survival motor neuron (SMN) protein-the loss of which causes the neuromuscular disease spinal muscular atrophy (SMA)-binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs that are enriched for translational enhancer sequences in the 5 ' untranslated region (UTR) and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins that are involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs encoding proteins that are relevant to SMA pathogenesis.Lauria et al. show that SMN, the loss of which causes spinal muscular atrophy (SMA), preferentially positions ribosomes within the first five codons of SMA-related mRNAs and enhances their translation.
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Lauria, Fabio; Bernabo, Paola; Tebaldi, Toma; Groen, Ewout Joan Nicolaas; Perenthaler, Elena; Maniscalco, Federica; Rossi, Annalisa; Donzel, Deborah; Clamer, Massimiliano; Marchioretto, Marta; Omersa, Neza; Orri, Julia; Dalla Serra, Mauro; Anderluh, Gregor; Quattrone, Alessandro; Inga, Alberto; Gillingwater, Thomas Henry; Viero, Gabriella
SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy / Lauria, Fabio; Bernabo, Paola; Tebaldi, Toma; Groen, Ewout Joan Nicolaas; Perenthaler, Elena; Maniscalco, Federica; Rossi, Annalisa; Donzel, Deborah; Clamer, Massimiliano; Marchioretto, Marta; Omersa, Neza; Orri, Julia; Dalla Serra, Mauro; Anderluh, Gregor; Quattrone, Alessandro; Inga, Alberto; Gillingwater, Thomas Henry; Viero, Gabriella. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 22:10(2020), pp. 1239-1251. [10.1038/s41556-020-00577-7]
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