CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN |
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Authors: | Vanesa Lafarga " target="_blank">Olga Tapia Sahil Sharma Rocio Bengoechea Georg Stoecklin Miguel Lafarga Maria T Berciano |
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Institution: | 1.Laboratory of Genomic Instability,“Centro Nacional de Investigaciones Oncológicas” (CNIO),Madrid,Spain;2.Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance,Heidelberg,Germany;3.Department of Anatomy and Cell Biology, “Centro de Investigación en Red de Enfermedades Neurodegenerativas” (CIBERNED),University of Cantabria-IDIVAL,Santander,Spain;4.Department of Biochemistry, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim,Heidelberg University,Mannheim,Germany;5.Center for Molecular Biology of Heidelberg University (ZMBH),Mannheim,Germany;6.German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance,Mannheim,Germany;7.Department of Neurology, The Hope Center for Neurological Diseases,School of Medicine of Washington University,St. Louis,USA |
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Abstract: | 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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