Cellular and Molecular Life Sciences

, Volume 75, Issue 3, pp 527–546 | Cite as

CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN

  • Vanesa Lafarga
  • Olga Tapia
  • Sahil Sharma
  • Rocio Bengoechea
  • Georg Stoecklin
  • Miguel Lafarga
  • Maria T. Berciano
Original Article


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.


Cajal bodies Nuclear speckles SMN SMA Protein acetylation CBP SMN complex SMN interactome SnRNP HDAC inhibitor 



Survival of motor neuron protein


Cajal body


Spinal muscular atrophy


Small nuclear ribonucleoprotein


CREB-binding protein


Promyelocytic leukemia protein


Histone deacetylases


Small nucleolar ribonucleoprotein


Precursor messenger RNA


Precursor ribosomal RNA


Small Cajal body-specific RNA


Post-translational modification


Small ubiquitin-like modifier 1


SUMO interacting motif


Trichostatin A


Suberoylanilide hydroxamic acid


Acetyl/SUMO acceptor lysine


Nuclear body


Fluorescence recovery after photobleaching


Mass spectrometry


Green fluorescence protein



The authors are indebted to Prof. Angus I. Lamond, Prof. Greg Matera, Prof. Maria Carmo-Fonseca and Prof. Larry Gerace for reagents, and Renate Voit (DKFZ) for generously providing plasmids. We would also like to acknowledge Dr. Thomas Ruppert and his team from the ZMBH (Zentrum für Molekulare Biologie der Universität Heidelberg) Mass Spectrometry Core Facility and Dr. Fidel Madrazo from the IDIVAL (Instituto de Investigación Sanitaria Valdecilla) Microscopy Facility. This work was supported by the following Grants: “Dirección General de Investigación” (BFU2014-54754-P) and “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED; CB06/05/0037) Spain. V. Lafarga was supported by a Marie Curie Intra-European Fellowship (mirnaAGOddr, Grant nr. 300384). O. Tapia was supported by a Postdoctoral Fellowship from SMA Europe and FundAME (Spain).

Author contributions

VL, OT and SS conceived experiments, performed transfection experiments and co-immunoprecipitation assays, VL, SS, and GS performed mass spectrometry analysis, RB performed mutagenesis, ML, MTB and GS designed experiments and wrote the manuscript.

Supplementary material

18_2017_2638_MOESM1_ESM.tif (47.9 mb)
Supplementary material 1 (TIFF 49085 kb) Figure A1. Expression of CBP induces cytoplasmic accumulation of endogenous SMN and interferes with CB biogenesis. (a) HEK293T cells were transfected with GFP or GFP–SMNwt alone or together with the CBP-HA. GFP-binder beads were used to purify GFP–SMNwt from cell lysates, and acetylation was examined using an anti-acetyl lysine (AcK) antibody by western blot analysis (b-c) MCF7 cells were transfected with either empty vector pcDNA-HA (b) or with CBP-HA (c) and 24 h later fixed and stained with anti-SMN. (d) quantitative and densitometric analysis of the CB number per cell (left) and cytoplasmic endogenous SMN fluorescence signal (right) in cells expressing empty vector (gray) or CBP-HA (orange). (e) Surface representation of the Tudor domain structure. Blue and red colors indicate positive and negative electrostatic surface potential, respectively. (f) Morphological differentiation of motor neurons NSC-34 cells by immunolabeling of the β-Tubulin isoform III. (g) NSC-34 cells were transfected with GFP–SMNwt and, after 24 h differentiation, were either left untreated or treated with TSA at 100 nM for 24 h. (h) NSC-34 cells were transfected with CBP-HA and, after differentiation, fixed and stained with anti-SMN. Scale bars: 10 μm (b, c) and 5 µm (f–h). Quantitative and densitometric analysis were performed in at least three independent experiments per group (n = 3). Each scatter dot plot represents the CB number per cells and cytoplasmic SMN intensity measured from at least 150 cells from each group. The horizontal black line within the scatter dot plots represents the mean for each group; ***p < 0.0001
18_2017_2638_MOESM2_ESM.tif (30 mb)
Supplementary material 2 (TIFF 30672 kb) Figure A2. (a) MCF7 cells expressing GFP–SMNK119R were untreated (left panel) treated with TSA (100 nM) for 16 h and fixed (middle panel) or allowed to recover in normal medium for 24 h (right panel). Cells were stained with anti-Coilin antibody. (b) quantitative analysis of the mean number of CBs per GFP–SMNK119R-positive cell, comparing non-treated (blue), TSA-treated (red) or after recovery for 24 h (yellow). (c) densitometric analysis of cytoplasmic fluorescence signal of GFP–SMNK119R (dark red) compared to GFP–SMNwt (red) in TSA-treated cells. (g-h) MCF7 cells co-transfected with GFP–SMNK119R and the empty vector pcDNA-HA (d) or CBP-HA (e) were fixed and stained with anti-HA antibody. (f) The graph represents the quantitative analysis of the mean CB number comparing cells co-expressing GFP–SMNK119R and the empty vector pcDNA-HA (blue) or CBP-HA (dark blue). (g) citoplasmic fluorescence signal (right) in cells co-expressing either GFP–SMNwt (orange) or GFP–SMNK119R (brown) and CBP-HA (orange). Scale bar 10 μm. Quantitative and densitometric analysis were performed in at least three independent experiments per group (n = 3). Each scatter dot plot represents the CB number per cells and cytoplasmic GFP–SMN intensity measured from at least 150 cells from each group. The horizontal black line within the scatter dot plots represents the mean for each group; *p < 0.01, ***p < 0.0001; n.s non significant data
18_2017_2638_MOESM3_ESM.docx (106 kb)
Supplementary material 3 (DOCX 105 kb) Table A1. List of proteins enriched on GFP–SMNwt sample versus GFP. The cutoff was set for those proteins that were enriched more than 50-folds on the GFP–SMNwt sample (versus GFP) and are represented for more 4 unique peptides
18_2017_2638_MOESM4_ESM.docx (116 kb)
Supplementary material 4 (DOCX 115 kb) Table A2. List of proteins enriched on GFP–SMNK119R sample versus GFP. The cutoff was set for those proteins that were enriched more than 50-folds on the GFP–SMNK119R sample (versus GFP) and are represented for more 4 unique peptides


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Authors and Affiliations

  1. 1.Laboratory of Genomic Instability“Centro Nacional de Investigaciones Oncológicas” (CNIO)MadridSpain
  2. 2.Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH AllianceHeidelbergGermany
  3. 3.Department of Anatomy and Cell Biology, “Centro de Investigación en Red de Enfermedades Neurodegenerativas” (CIBERNED)University of Cantabria-IDIVALSantanderSpain
  4. 4.Department of Biochemistry, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  5. 5.Center for Molecular Biology of Heidelberg University (ZMBH)MannheimGermany
  6. 6.German Cancer Research Center (DKFZ), DKFZ-ZMBH AllianceMannheimGermany
  7. 7.Department of Neurology, The Hope Center for Neurological DiseasesSchool of Medicine of Washington UniversitySt. LouisUSA

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