Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation.
TTDN1
brittle hair phenotype
epithelial barrier function
mRNA splicing
skin differentiation
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 11 2023
08 11 2023
Historique:
revised:
15
09
2023
received:
10
05
2023
accepted:
18
09
2023
medline:
9
11
2023
pubmed:
6
10
2023
entrez:
6
10
2023
Statut:
ppublish
Résumé
The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.
Identifiants
pubmed: 37800682
doi: 10.15252/emmm.202317973
pmc: PMC10630875
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
MPLKIP protein, human
0
Dbr1 protein, human
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e17973Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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