Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization.
Fiche publication
Date publication
janvier 2021
Journal
eLife
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
Tous les auteurs :
Gori I, George R, Purkiss AG, Strohbuecker S, Randall RA, Ogrodowicz R, Carmignac V, Faivre L, Joshi D, Kjaer S, Hill CS
Lien Pubmed
Résumé
Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Mots clés
biochemistry, chemical biology, chromosomes, gene expression, human
Référence
Elife. 2021 Jan 8;10: