Journal
NATURE CELL BIOLOGY
Volume 22, Issue 10, Pages 1239-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-020-00577-7
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Funding
- Provincia Autonoma di Trento, Italy (AxonomiX research project)
- UK SMA Research Consortium, SMA Europe
- Wellcome Trust [106098/Z/14/Z]
- Stichting Spieren voor Spieren (the Netherlands)
- Slovenian Research Agency [P1-0391]
- COST Action [CA15126]
- AFM-Telethon [22129]
- Caritro Foundation (young post-doc funding grant)
- Telethon [GGP19115]
- IMMAGINA Biotechnology (Italy)
- Wellcome Trust [106098/Z/14/Z] Funding Source: Wellcome Trust
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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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