CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN
The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2018
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| In: |
Cellular and molecular life sciences
Year: 2018, Volume: 75, Issue: 3, Pages: 527-546 |
| ISSN: | 1420-9071 |
| DOI: | 10.1007/s00018-017-2638-2 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1007/s00018-017-2638-2 Verlag, Volltext: https://doi.org/10.1007/s00018-017-2638-2 
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| Author Notes: | Vanesa Lafarga, Olga Tapia, Sahil Sharma, Rocio Bengoechea, Georg Stoecklin, Miguel Lafarga, Maria T. Berciano |
| Summary: | The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels. |
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| Item Description: | Gesehen am 03.09.2018 06 September 2017 |
| Physical Description: | Online Resource |
| ISSN: | 1420-9071 |
| DOI: | 10.1007/s00018-017-2638-2 |