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oai:repisalud.isciii.es:20.500.12105/260852025-12-18T12:56:23Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Lafarga, Vanesa author Tapia, Olga author Sharma, Sahil author Bengoechea, Rocio author Stoecklin, Georg author Lafarga, Miguel author Berciano, Maria T author 2018-02 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. Cell Mol Life Sci . 2018 Feb;75(3):527-546. Cell Mol Life Sci 28879433 https://hdl.handle.net/20.500.12105/26085 CBP Cajal bodies HDAC inhibitor Nuclear speckles Protein acetylation SMA SMN SMN complex SMN interactome SnRNP CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.