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

https://www.ncbi.nlm.nih.gov/pubmed/33416497

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.