TY  - JOUR
AU  - Lafarga, Vanesa
AU  - Tapia, Olga
AU  - Sharma, Sahil
AU  - Bengoechea, Rocio
AU  - Stoecklin, Georg
AU  - Lafarga, Miguel
AU  - Berciano, Maria T
TI  - CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.
JO  - Cellular and molecular life sciences
VL  - 75
IS  - 3
SN  - 1420-9071
CY  - Basel
PB  - Birkhäuser
M1  - DKFZ-2018-00082
SP  - 527 - 546
PY  - 2018
N1  - DKFZ-ZMBH-Allianz
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:28879433
DO  - DOI:10.1007/s00018-017-2638-2
UR  - https://inrepo02.dkfz.de/record/131785
ER  -