Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization.
Activin
Marfan syndrome
SKI
SMAD
Shprintzen-Goldberg syndrome
TGF-β
biochemistry
chemical biology
chromosomes
gene expression
human
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
08 01 2021
08 01 2021
Historique:
received:
28
09
2020
accepted:
07
01
2021
pubmed:
9
1
2021
medline:
29
1
2022
entrez:
8
1
2021
Statut:
epublish
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 co-repressor SKI, which is a negative regulator of TGF-β 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, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Identifiants
pubmed: 33416497
doi: 10.7554/eLife.63545
pii: 63545
pmc: PMC7834018
doi:
pii:
Substances chimiques
DNA-Binding Proteins
0
Proto-Oncogene Proteins
0
Transforming Growth Factor beta
0
SKI protein, human
126648-96-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001095
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Informations de copyright
© 2021, Gori et al.
Déclaration de conflit d'intérêts
IG, RG, AP, SS, RR, RO, VC, LF, DJ, SK, CH No competing interests declared
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